Preparation method of 4-methoxycinnamic acid-2-ethylhexyl ester
The toxicity of 4-methoxycinnamic acid-2-ethylhexyl acetate in the prior art was solved by the reaction of 2-ethylhexyl acetate and 4-methoxybenzaldehyde under the catalyzed sodium tert-butoxide. The complex raw materials and processes and pollution problems have achieved efficient, low temperature and low toxic synthesis processes, with high yield and environmental protection advantages.
Patent Information
- Application Number
- CN202411383035.8
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-09-30
- Publication Date
- 2025-01-07
AI Technical Summary
The method for preparing 4-methoxycinnamic acid-2-ethylhexyl ester in the prior art has problems such as the use of toxic raw materials, complicated process, unsatisfactory yields, and serious pollution, which limits its industrial application.
4-methoxycinnamic acid-2-ethylhexyl acetate and 4-methoxybenzaldehyde were used to prepare 4-methoxycinnamic acid-2-ethylhexyl ester by reacting the reaction conditions and catalyst ratio. Highly efficient, low temperature and low toxic synthesis process.
This method has high product yield, few steps and simple equipment, which reduces wastewater generation and environmental pollution, and has good practical application prospects.
Smart Images
Figure CN119263984A_ABST
Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of organic synthesis and relates to a method for preparing 4-methoxycinnamic acid-2-ethylhexyl ester. Background Art
[0002] Ultraviolet rays always exist in the atmosphere, and the harm of ultraviolet rays to the human body has attracted more and more attention. UVB (280-320nm) in ultraviolet rays can easily cause sunburn on the skin, and in a short period of time, it will cause acute damage to the skin such as erythema and blisters, which is medically called "sun dermatitis". 4-methoxycinnamic acid-2-ethylhexyl ester (OMC) is one of the most commonly used sunscreens in the world. It is a good absorber of ultraviolet rays in the UVB region. It can effectively prevent ultraviolet rays of 280-330nm, and has a high absorption rate, no irritation to the skin, good safety, and good solubility in oily raw materials. It is almost an ideal sunscreen. It is often used in the preparation of skin care cosmetics such as sunscreen (cream, lotion, liquid), which can effectively absorb ultraviolet rays in the sun to prevent human skin from getting red, sunburned, and tanned. It is also a therapeutic drug for photodermatitis. OMC is also widely used in daily chemical plastics, rubber and coatings.
[0003] At present, 4-methoxycinnamic acid-2-ethylhexyl ester (0OMC) is mainly prepared by the following routes:
[0004] 1. Prepared by diazotization reaction using 4-methoxyaniline as raw material:
[0005] The aromatic amine is first reacted with HBF4 and NaNO2 to generate a stable diazonium salt, and then coupled with an acrylic acid derivative under the action of a Pd / base catalyst to obtain a 4-methoxycinnamate derivative with a high yield. The above methods all use aromatic amines as raw materials, which are toxic and should be avoided as much as possible during the production process.
[0006] 2. Prepared by Heck coupling reaction using 4-methoxyhalobenzene as raw material:
[0007] The main method is to obtain the corresponding 4-methoxycinnamic acid derivatives by Heck coupling reaction between olefinic acid derivatives and halogenated aromatic hydrocarbons under palladium catalysis. For example, 4-methoxyhalobenzene is used as a raw material, and a coupling reaction is carried out with an acrylic acid derivative under the action of a Pd / base catalyst to generate a 4-methoxycinnamic acid derivative. The synthesis process is cumbersome and the yield is not ideal.
[0008] 3. Prepared by Claisen-Schmidt reaction using 4-methoxybenzaldehyde as raw material:
[0009] Dissolve 4-methoxybenzaldehyde and methyl acetate in a conventional hydrocarbon solvent, use a strong base such as sodium methoxide as a catalyst to catalyze the reaction, react at 40°C-65°C for 2-6h to obtain a mixture, and then acidify it with a polybasic strong acid. In the presence of a polybasic acid salt, esterification or transesterification reaction occurs with alcohol to obtain the corresponding 4-methoxycinnamate. After the reaction is completed, a large amount of water is needed to wash the material. The high-salt and high-COD wastewater produced in this way puts pressure on environmental protection treatment and causes pollution to the surrounding environment.
[0010] 4. Prepared by Perkin reaction using 4-methoxybenzaldehyde as raw material:
[0011] The Perkin reaction is to use aromatic aldehydes and acid anhydrides to obtain unsaturated acids under the catalytic conditions of strong bases. Because it is a relatively cheap raw material, it is often used in production. The Perkin reaction is one of the commonly used methods for preparing cinnamic acid derivatives. For example, 4-methoxybenzaldehyde and acetic anhydride react with strong bases to generate 4-methoxycinnamic acid, which is then esterified with alcohol to obtain the corresponding esters. Of course, it can also react to generate low-grade vinegar first, and then prepare high-grade esters through ester exchange reaction. The reaction temperature of this process is relatively high, the yield is less than 70%, and a large amount of useless NaCl and dilute acetic acid are also produced. At the same time, a large amount of acetate, carbonate and inorganic acid are used in the reaction process, which will produce a large amount of high-salt and high-COD value wastewater, which will bring serious problems to pollution control.
[0012] 5. Prepared by Knoevenage1 reaction using 4-methoxybenzaldehyde as raw material:
[0013] This reaction is an improvement of the Perkin reaction. It changes the anhydride into an active methylene compound containing electron-withdrawing, and uses an organic weak base such as pyridine as the catalyst. This method requires a low temperature and has a good yield. Then, the higher ester is prepared by transesterification. To prepare 4-methoxycinnamic acid, after the reaction, acid water washing is required to remove the catalyst piperidine. These operations will undoubtedly produce a large amount of wastewater, which will seriously pollute the environment. Then, OMC is obtained by esterification with isooctyl alcohol, but malonic acid and its derivatives are expensive, and the catalysts used, such as pyridine, have a strong odor and are highly toxic, which limits the possibility of this method being applied to industrial production. Summary of the invention
[0014] In view of the shortcomings of the prior art, the object of the present invention is to provide a clean synthesis process for 2-ethylhexyl 4-methoxycinnamate (OMC) which is different from that reported in previous literature.
[0015] To achieve this object, the present invention adopts the following technical solutions:
[0016] In one aspect, the present invention provides a method for preparing 2-ethylhexyl 4-methoxycinnamate, the method comprising the following steps:
[0017] 2-Ethylhexyl acetate reacts with 4-methoxybenzaldehyde in the presence of a catalyst to obtain 2-ethylhexyl 4-methoxycinnamate, wherein the catalyst is sodium tert-butoxide, and the reaction formula is as follows:
[0018]
[0019] In the present invention, the use of sodium tert-butoxide as a catalyst can make the reaction more thorough, the reaction efficiency is higher, and the product yield is high. In the present invention, inorganic bases such as sodium hydroxide and potassium hydroxide are selected, but they do not react because of their weak alkalinity. If sodium methoxide is used, the free methoxy group will replace 2-ethylhexyl alcohol, and NaH has a high risk factor, and n-BuLi (n-butyl lithium) and LDA (diisopropyl lithium amide) are too expensive.
[0020] Preferably, the molar ratio of 4-methoxybenzaldehyde to 2-ethylhexyl acetate is 1:3-1:5, for example, 1:3, 1:3.3, 1:3.5, 1:3.8, 1:4, 1:4.5, 1:4.8 or 1:5, etc.
[0021] Preferably, the molar ratio of 4-methoxybenzaldehyde to the catalyst is 1:1.3-1:1.5, for example 1:1.2, 1:1.3, 1:1.35, 1:1.38, 1:1.4, 1:1.43, 1:1.45 or 1:1.5.
[0022] Preferably, the reaction is carried out in a solvent, and the solvent is selected from any one or a combination of at least two of ethylene glycol dimethyl ether, toluene, THF, diethyl ether or methyl tert-butyl ether.
[0023] Preferably, the specific operation of the reaction is:
[0024] (1) dissolving 2-ethylhexyl acetate in a solvent, adding sodium tert-butoxide to the system, and stirring to mix;
[0025] (2) Dissolving 4-methoxybenzaldehyde in a solvent to obtain a solution, adding the solution to a reaction system, and reacting to obtain the 4-methoxycinnamic acid-2-ethylhexyl ester.
[0026] Preferably, the reactions in step (1) and step (2) are carried out under nitrogen protection.
[0027] Preferably, the sodium tert-butoxide in step (1) is added in batches. Adding sodium tert-butoxide will release a large amount of heat, and adding it all at once will cause transesterification with 2-ethylhexyl acetate.
[0028] Preferably, the sodium tert-butoxide is added in 5-10 batches (eg, 5 batches, 6 batches, 7 batches, 8 batches, 9 batches or 10 batches).
[0029] Preferably, the sodium tert-butoxide in step (1) is added at a temperature of -20°C to -10°C (eg, -20°C, -18°C, -15°C, -13°C or -10°C).
[0030] Preferably, the stirring and mixing in step (1) is carried out at -20°C to -10°C (e.g., -20°C, -18°C, -15°C, -13°C or -10°C), and the stirring time is 2 to 3 hours (e.g., 2 hours, 2.3 hours, 2.5 hours, 2.8 hours or 3 hours).
[0031] Preferably, the solution of 4-methoxybenzaldehyde in step (2) is added to the reaction system at a temperature of -20°C to -10°C (eg, -20°C, -18°C, -15°C, -13°C or -10°C).
[0032] Preferably, the reaction temperature in step (2) is 0-10°C, such as 0°C, 2°C, 4°C, 6°C, 8°C or 10°C.
[0033] Preferably, the reaction time of step (2) is 2 to 3 h, for example 2 h, 2.3 h, 2.5 h, 2.8 h or 3 h.
[0034] As a preferred technical solution, the preparation method of 4-methoxycinnamic acid-2-ethylhexyl ester of the present invention comprises the following steps:
[0035] (1) dissolving 2-ethylhexyl acetate in a solvent, replacing the solvent with nitrogen under reduced pressure three times, adding sodium tert-butoxide to the system in batches at -20°C to -10°C, and stirring at -20°C to -10°C for 2 to 3 hours;
[0036] (2) dissolving 4-methoxybenzaldehyde in a solvent to obtain a solution, adding the solution to the reaction system at -20°C to -10°C, and reacting at 0°C to 10°C for 2 to 3 hours to obtain the 4-methoxycinnamic acid-2-ethylhexyl ester;
[0037] The molar ratio of the 4-methoxybenzaldehyde to 2-ethylhexyl acetate is 1:3-1:5, the molar ratio of the 4-methoxybenzaldehyde to the catalyst is 1:1.2-1:1.5, and the solvent is selected from any one of ethylene glycol dimethyl ether, toluene, THF, diethyl ether or methyl tert-butyl ether, or a combination of at least two thereof.
[0038] Compared with the prior art, the present invention has the following beneficial effects:
[0039] The present invention uses 4-methoxycinnamic acid and 2-ethylhexyl acetate as starting materials and sodium tert-butoxide as a catalyst. The route has the characteristics of fewer steps, mild reaction conditions, simple equipment, etc., and has good practical application prospects. The catalyst of the present invention makes the reaction more thorough, the reaction efficiency is higher, and the product yield is high. BRIEF DESCRIPTION OF THE DRAWINGS
[0040] Figure 1 The following is the H NMR spectrum of the product prepared in Example. DETAILED DESCRIPTION
[0041] The technical solution of the present invention is further described below by specific implementation methods. It should be understood by those skilled in the art that the embodiments are only to help understand the present invention and should not be regarded as specific limitations of the present invention.
[0042] Example 1
[0043] In this embodiment, a method for preparing 2-ethylhexyl 4-methoxycinnamate is provided, and the preparation method comprises the following steps:
[0044] 1. Add 2-ethylhexyl acetate (900 ml, 4.5 eq) and ethylene glycol dimethyl ether (400 ml) into a 2000 ml three-necked flask at once, and replace the atmosphere with nitrogen under reduced pressure for 3 times;
[0045] 2. Lower the reaction temperature to -15°C, add sodium tert-butoxide (182 g, 1.3 eq) to the reaction in 5 batches to control the reaction temperature not exceeding -10°C; after the addition, control the reaction temperature to -15°C and stir for 2 hours;
[0046] 3. Dissolve 4-methoxybenzaldehyde (200g, 1.0eq) in ethylene glycol dimethyl ether (200ml), and drip the solution into the reaction, controlling the reaction temperature to -15°C. After dripping, return the reaction temperature to 5°C and stir for 2.0h, take a sample and test HPLC to find that 4-methoxybenzaldehyde is ≤1.0%;
[0047] 4. Add the reaction solution to ice water (1000 ml) to quench the reaction, stir for 20 minutes, let stand, and separate the lower aqueous phase. Add 1.0N HCl aqueous solution (500 ml) to the organic phase and wash once. Wash the organic phase again with a clean aqueous solution (500 ml).
[0048] 5. The organic phase was concentrated under reduced pressure (pressure: -0.01 MPa, temperature: 220°C) to obtain 350 g of product with a purity of 99.2% and a yield of 82.2%.
[0049] The product was characterized by H NMR spectroscopy (300 MHz, the deuterated reagent used was deuterated DMSO), and its H NMR spectrum was as follows: Figure 1 shown.
[0050] Example 2
[0051] 1. Add 2-ethylhexyl acetate (900 ml, 4.5 eq) and ethylene glycol dimethyl ether (400 ml) into a 2000 ml three-necked flask at once, and replace the atmosphere with nitrogen under reduced pressure for 3 times;
[0052] 2. Lower the reaction temperature to -20°C, add sodium tert-butoxide (182 g, 1.2 eq) to the reaction in batches to control the reaction temperature not exceeding -10°C; after the addition, control the reaction temperature to -20°C and stir for 3 hours;
[0053] 3. Dissolve 4-methoxybenzaldehyde (200g, 1.0eq) in ethylene glycol dimethyl ether (200ml, 1.0v / wt), and drip the solution into the reaction, controlling the reaction temperature to -20°C. After dripping, return the reaction temperature to 0°C and stir for 2.0h, take a sample for HPLC detection, if 4-methoxybenzaldehyde is ≤1.0%, proceed to the next step, otherwise, continue to keep warm for 2.0 hours;
[0054] 4. Add the reaction solution to ice water (1000 ml) to quench the reaction, stir for 20 minutes, let stand, and separate the lower aqueous phase. Add 1.0N HCl aqueous solution (500 ml) to the organic phase and wash once. Wash the organic phase again with a clean aqueous solution (500 ml).
[0055] 5. The organic phase was concentrated under reduced pressure (pressure: -0.01 MPa, temperature: 220°C) to obtain 347 g of product with a purity of 99.0% and a yield of 81.4%.
[0056] Example 3
[0057] 1. Add 2-ethylhexyl acetate (800 ml, 4.0 eq) and ethylene glycol dimethyl ether (400 ml) into a 2000 ml three-necked flask at once, and replace the atmosphere with nitrogen under reduced pressure for 3 times;
[0058] 2. Lower the reaction temperature to -10°C, add sodium tert-butoxide (182 g, 1.3 eq) to the reaction in 5 batches to control the reaction temperature not exceeding -10°C; after the addition, control the reaction temperature to -10°C and stir for 2 hours;
[0059] 3. Dissolve 4-methoxybenzaldehyde (200g, 1.0eq) in ethylene glycol dimethyl ether (200ml), and drip the solution into the reaction, controlling the reaction temperature to -15°C. After dripping, return the reaction temperature to 5°C and stir for 2h, take samples for HPLC detection, if 4-methoxybenzaldehyde is ≤1.0%, proceed to the next step, otherwise, continue to keep warm for 2.0 hours;
[0060] 4. Add the reaction solution to ice water (1000 ml) to quench the reaction, stir for 20 minutes, let stand, and separate the lower aqueous phase. Add 1.0N HCl aqueous solution (500 ml) to the organic phase and wash once. Wash the organic phase with a clean aqueous solution (500 ml).
[0061] 5. The organic phase was concentrated under reduced pressure (pressure: -0.01 MPa, temperature: 220°C) to obtain 340.8 g of product with a purity of 99.1% and a yield of 80.0%.
[0062] Comparative Example 1
[0063] The difference from Example 1 is that the sodium tert-butoxide in Example 1 is replaced with an equal amount of sodium hydroxide. The remaining steps are the same as in Example 1, and the result is 0 g of the product, and no reaction occurs, and the product cannot be obtained.
[0064] Comparative Example 2
[0065] The difference from Example 1 is that the sodium tert-butoxide in Example 1 is replaced with an equal amount of triethylamine. The remaining steps are the same as in Example 1, and the result is 0 g of the product, and no reaction occurs, and the product cannot be obtained.
[0066] Comparative Example 3
[0067] The difference from Example 1 is that the sodium tert-butoxide in Example 1 is replaced by an equal amount of sodium methoxide. The remaining steps are the same as those in Example 1, and 300 g of the product is obtained with a purity of 99.0% and a yield of 70%.
[0068] Comparative Example 4
[0069] The difference from Example 1 is that the sodium tert-butoxide in Example 1 is replaced with an equal amount of SDA (NHS-diaziridine). The remaining steps are the same as in Example 1, and the result is 0 g of the product, and no reaction occurs, and the product cannot be obtained.
[0070] Comparative Example 5
[0071] The difference from Example 1 is that the sodium tert-butoxide in Example 1 is replaced by sodium hydride of the same substance mass. The remaining steps are the same as those in Example 1, and the product 320 g is obtained with a purity of 99.3% and a yield of 75.1%. Although sodium hydride makes the product yield higher, it has a high risk factor.
[0072] The applicant declares that the present invention illustrates the preparation method of the present invention through the above-mentioned embodiments, but the present invention is not limited to the above-mentioned embodiments, that is, it does not mean that the present invention must rely on the above-mentioned embodiments to be implemented. Those skilled in the art should understand that any improvement of the present invention, equivalent replacement of various raw materials of the product of the present invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.
Claims
1. A method for preparing 2-ethylhexyl 4-methoxycinnamate, characterized in that: The preparation method comprises the following steps: 2-Ethylhexyl acetate reacts with 4-methoxybenzaldehyde in the presence of a catalyst to obtain 2-ethylhexyl 4-methoxycinnamate, wherein the catalyst is sodium tert-butoxide.
2. The preparation method according to claim 1, characterized in that: The molar ratio of the 4-methoxybenzaldehyde to 2-ethylhexyl acetate is 1:3-1:
5.
3. The preparation method according to claim 1 or 2, characterized in that: The molar ratio of the 4-methoxybenzaldehyde to the catalyst is 1:1.2-1:1.
5.
4. The preparation method according to any one of claims 1 to 3, characterized in that The reaction is carried out in a solvent, and the solvent is selected from any one of ethylene glycol dimethyl ether, toluene, THF, diethyl ether or methyl tert-butyl ether, or a combination of at least two thereof.
5. The preparation method according to any one of claims 1 to 4, characterized in that: The specific operation of the reaction is: (1) dissolving 2-ethylhexyl acetate in a solvent, adding sodium tert-butoxide to the system, and stirring to mix; (2) Dissolving 4-methoxybenzaldehyde in a solvent to obtain a solution, adding the solution to a reaction system, and reacting to obtain the 4-methoxycinnamic acid-2-ethylhexyl ester.
6. The preparation method according to claim 5, characterized in that: The reactions in step (1) and step (2) are carried out under nitrogen protection; Preferably, the sodium tert-butoxide in step (1) is added in batches; Preferably, the sodium tert-butoxide is added in 5-10 batches; Preferably, the sodium tert-butoxide in step (1) is added at a temperature of -20°C to -10°C.
7. The preparation method according to claim 5 or 6, characterized in that: The stirring and mixing in step (1) is carried out at -20°C to -10°C, and the stirring time is 2 to 3 hours.
8. The preparation method according to any one of claims 5 to 7, characterized in that: In step (2), the 4-methoxybenzaldehyde solution is added into the reaction system at a temperature of -20°C to -10°C.
9. The preparation method according to any one of claims 5 to 8, characterized in that: The reaction temperature in step (2) is 0 to 10°C; Preferably, the reaction time in step (2) is 2-3 h.
10. The preparation method according to any one of claims 1 to 9, characterized in that: The preparation method comprises the following steps: (1) dissolving 2-ethylhexyl acetate in a solvent, replacing the solvent with nitrogen under reduced pressure three times, adding sodium tert-butoxide to the system in batches at -20°C to -10°C, and stirring at -20°C to -10°C for 2 to 3 hours; (2) dissolving 4-methoxybenzaldehyde in a solvent to obtain a solution, adding the solution to the reaction system at -20°C to -10°C, and reacting at 0°C to 10°C for 2-3 hours to obtain the 4-methoxycinnamic acid-2-ethylhexyl ester; The molar ratio of the 4-methoxybenzaldehyde to 2-ethylhexyl acetate is 1:3-1:5, the molar ratio of the 4-methoxybenzaldehyde to the catalyst is 1:1.2-1:1.5, and the solvent is selected from any one of ethylene glycol dimethyl ether, toluene, THF, diethyl ether or methyl tert-butyl ether, or a combination of at least two thereof.