A method for preparing 2,4-dihydroxyacetophenone using acetaldehyde as an acetyl source
By using acetaldehyde as the acetyl source for free radical acylation reaction and employing BPO and NHPI catalysts, the environmental pollution and metal residue problems in the traditional preparation of 2,4-dihydroxyacetophenone have been solved, achieving high-purity and high-yield preparation suitable for industrial applications.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2026-06-11
- Publication Date
- 2026-07-10
AI Technical Summary
Existing methods for preparing 2,4-dihydroxyacetophenone have drawbacks such as severe environmental pollution, significant metal residue problems, harsh reaction conditions, or excessively high production costs, making it difficult to meet the requirements of modern green chemistry and the pharmaceutical industry for high-purity, low-residue, and environmentally friendly production processes.
2,4-Dihydroxyacetophenone was prepared by free radical acylation reaction without transition metals, using acetaldehyde as the acetyl source. Benzoyl peroxide (BPO) was used as the oxidant and N-hydroxyphthalimide (NHPI) as the catalyst, and the reaction was carried out with resorcinol. The use of transition metal salts was avoided, and the reaction temperature was 65-85℃.
This method enables the preparation of 2,4-dihydroxyacetophenone with high purity and high yield, avoiding heavy metal residues, reducing production costs, simplifying equipment requirements, reducing environmental pollution, and making it suitable for industrial applications.
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Figure CN122355799A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to a method for preparing 2,4-dihydroxyacetophenone using acetaldehyde as the acetyl source, belonging to the fields of pharmaceutical intermediates and fine chemical technology. Background Technology
[0002] 2,4-Dihydroxyacetophenone, also known as resorcinol acetophenone, is an important fine chemical intermediate widely used in pharmaceuticals, pesticides, cosmetics, catalysts, and analytical testing. In the pharmaceutical industry, it is a key intermediate for the synthesis of coronary heart disease drugs such as ethoxyflavonoids, anti-gout drugs such as chalcone derivatives, and antibacterial drugs such as benzoxazine Schiff base derivatives. In the cosmetics industry, it is a precursor for the synthesis of the highly effective tyrosinase inhibitor thiazolysorcinol, possessing excellent whitening effects. In analytical testing, it is an important colorimetric reagent for determining metal ions such as iron and zirconium ions.
[0003] Currently, the preparation of 2,4-dihydroxyacetophenone mainly employs the Friedel-Crafts electrophilic acylation reaction (also known as the Nencki reaction), which uses resorcinol as a raw material and acetic acid, acetic anhydride, and acetyl chloride as acetyl sources, directly Friedel-Crafts acylation under the action of metal chlorides (such as anhydrous zinc chloride). This method has the following disadvantages: 1) The reaction requires an excess of metal chloride as a promoter, generating a large amount of wastewater containing transition metal salts, which is difficult to recover and seriously pollutes the environment. 2) The reaction system is strongly acidic, which is highly corrosive to the reaction equipment, increasing equipment investment and maintenance costs. 3) It easily generates diacetylation byproducts, requiring multiple recrystallizations to obtain high-purity products, reducing the overall yield. 4) The product inevitably contains heavy metal residues such as zinc ions, requiring complex purification steps to meet the quality requirements of pharmaceutical-grade products. 5) The reaction conditions are harsh, requiring a high temperature of 135-140℃, resulting in high energy consumption.
[0004] To address the shortcomings of traditional methods, researchers have developed various improved approaches. For example, using sulfuric acid, phosphoric acid, or polyphosphoric acid as catalysts and removing water generated during the reaction via azeotropic distillation can improve conversion rates. However, these methods require high reaction temperatures (140-160℃) and are prone to side reactions that generate diacetylated products. Another approach uses supported catalysts such as PO / SiO2, methanesulfonic acid-acidic alumina, and methanesulfonic acid-graphite. While these catalysts are recyclable, the reaction temperature still needs to be 120-150℃, and the yield is low. Furthermore, catalyst preparation is complex and costly. Finally, methods such as the Fries rearrangement, Heck reaction, and alcohol oxidation, while offering improvements in some aspects, suffer from low yields, expensive raw materials, and numerous reaction steps, making them difficult to apply to industrial production.
[0005] In summary, existing methods for preparing 2,4-dihydroxyacetophenone generally suffer from severe environmental pollution, significant metal residue problems, harsh reaction conditions, or excessively high production costs, failing to meet the requirements of modern green chemistry and the pharmaceutical industry for high-purity, low-residue, and environmentally friendly production processes. Therefore, developing a new method for preparing 2,4-dihydroxyacetophenone that is free of transition metals, has mild reaction conditions, high selectivity, and is environmentally friendly has significant theoretical and practical value. Summary of the Invention
[0006] This invention provides a method for preparing 2,4-dihydroxyacetophenone using acetaldehyde as the acetyl source. The method uses aldehyde as the acetyl source and prepares 2,4-dihydroxyacetophenone through a transition metal radical-free acylation reaction. This method is green, environmentally friendly, and has a high yield and high purity.
[0007] To solve the above-mentioned technical problems, the technical solution adopted by the present invention is as follows:
[0008] A method for preparing 2,4-dihydroxyacetophenone using acetaldehyde as the acetyl source involves a direct free radical acylation reaction of acetaldehyde with resorcinol in the presence of an oxidant and a catalyst to obtain 2,4-dihydroxyacetophenone. No transition metal salts are required during the reaction.
[0009] Traditionally, it has been believed that the acylation of electron-rich aromatic rings can only proceed through electrophilic substitution mechanisms. However, this application breaks with conventional thinking, achieving this transformation efficiently through a free radical mechanism. Furthermore, this application overcomes the problem of traditional electrophilic substitution reactions easily generating diacetylated products by synergistic regulation of electronic effects and steric hindrance, significantly improving the selectivity of monoacetylation.
[0010] To improve the yield and purity of 2,4-dihydroxyacetophenone, the oxidant used is benzoyl peroxide (BPO); the catalyst is N-hydroxyphthalimide (NHPI). This application uses BPO as the oxidant, which can efficiently oxidize NHPI to PINO radicals without over-oxidizing resorcinol or the product.
[0011] To further improve the yield of 2,4-dihydroxyacetophenone, the molar ratio of oxidant to resorcinol is (0.1~2):2, preferably (1.5~2):2.
[0012] To improve the yield of 2,4-dihydroxyacetophenone, the molar ratio of catalyst to resorcinol is (0.1~2):2, preferably (0.15~0.25):2.
[0013] To ensure the yield of 2,4-dihydroxyacetophenone, the molar ratio of acetaldehyde to resorcinol is (4~6):2, preferably (5.5~6):2.
[0014] To balance the yield and energy consumption of 2,4-dihydroxyacetophenone, the preferred reaction temperature is 65-85℃ and the reaction time is 4-6h.
[0015] The reaction in this application (including heating, reaction, and cooling after the reaction) is carried out under reflux conditions.
[0016] The reaction in this application is carried out in a solvent.
[0017] To improve product yield, toluene or chlorobenzene is preferred solvent, with toluene being more preferred.
[0018] As a specific preferred method, the preparation method of 2,4-dihydroxyacetophenone is as follows: resorcinol, acetaldehyde, N-hydroxyphthalimide (NHPI) and benzoyl peroxide (BPO) are added to an organic solvent, and the mixture is refluxed at 65~85℃ for 4-6 hours. After the reaction is completed, the mixture is cooled, separated and purified to obtain 2,4-dihydroxyacetophenone.
[0019] To further improve the yield, as another specific preferred embodiment, a method for preparing 2,4-dihydroxyacetophenone using acetaldehyde as the acetyl source is characterized by comprising the following steps:
[0020] 1) Add resorcinol, acetaldehyde and N-hydroxyphthalimide to an organic solvent and heat to 65~85℃;
[0021] 2) Dissolve benzoyl peroxide in a solvent and add it dropwise to the reaction solution obtained in step 1). Reflux the reaction at 65~85℃ for 4-6 hours (the reaction time includes the time for adding benzoyl peroxide). After the reaction is completed, cool the solution, separate and purify it to obtain 2,4-dihydroxyacetophenone.
[0022] The above separation and purification process involves removing the solvent by distillation and recrystallizing 1-3 times with ethanol to obtain 2,4-dihydroxyacetophenone. The procedure is simple and yields high purity.
[0023] The above method significantly improves monoacetylation selectivity and reduces or avoids the formation of diacetylation byproducts through the synergistic regulation of electronic effects and steric hindrance. Furthermore, the reaction conditions are mild, proceeding efficiently at 60-80℃, with good substrate stability, few side reactions, and no need for azeotropic dehydration (existing Friedel-Crafts reactions are reversible and require continuous removal of generated water to improve conversion), simplifying equipment and operation. Post-treatment is simple; after the reaction, solvent and unreacted acetaldehyde can be removed by simple distillation.
[0024] The above method completely avoids the use of Lewis acid catalysts such as ZnCl2, AlCl3, and FeCl3. The product contains no heavy metal residues and does not require complicated metal removal and purification steps, directly meeting the requirements of pharmaceutical-grade products. Furthermore, the reaction does not use or produce acidic byproducts such as hydrogen chloride and sulfuric acid, and the equipment corrosion problem is completely eliminated.
[0025] This application uses acetaldehyde as the acetyl source, which is low in cost, highly reactive, environmentally friendly, and produces no acidic or toxic byproducts (the reaction of acetic anhydride and acetyl chloride will produce acetic acid and hydrogen chloride respectively, which need to be neutralized with alkali and produce a large amount of saline wastewater; the reaction of acetonitrile will produce ammonia, which requires the treatment of ammonia-containing wastewater).
[0026] Unless otherwise specified and not explicitly defined or agreed upon in this application, all percentages in this application refer to percentages by mass.
[0027] Any techniques not mentioned in this invention are based on existing technologies.
[0028] This invention discloses a method for preparing 2,4-dihydroxyacetophenone using acetaldehyde as the acetyl source. Using acetaldehyde as the acetyl source, and under the combined action of N-hydroxyphthalimide (NHPI) and benzoyl peroxide (BPO), resorcinol undergoes a highly efficient free radical acylation reaction to prepare 2,4-dihydroxyacetophenone in one step. This method eliminates the need for any transition metal salts, completely solving the environmental pollution and metal residue problems associated with traditional methods. The reaction conditions are mild, require no special equipment, exhibit high selectivity, are non-corrosive, produce high-purity products, and have low production costs, thus possessing broad industrial application prospects. Attached Figure Description
[0029] Figure 1 The 1H NMR spectrum of 2,4-dihydroxyacetophenone obtained in Example 1 ( 1 H NMR 400 MHz, CDCl3).
[0030] Figure 2 The image shown is the FT-IR infrared image of the 2,4-dihydroxyacetophenone core obtained in Example 1. Detailed Implementation
[0031] To better understand the present invention, the following embodiments further illustrate the content of the present invention, but the content of the present invention is not limited to the following embodiments.
[0032] In each case, unless otherwise specified, the temperature was at room temperature (15~25℃); unless otherwise specified, the pressure was at atmospheric pressure; unless otherwise specified, the stirring speed was 200 rpm.
[0033] Yield = Actual product mass / Theoretical product mass × 100%.
[0034] Example 1
[0035]
[0036] To a 2500 mL round-bottom flask equipped with a reflux condenser, 220.2 g (2 mol) of resorcinol, 1500 mL of toluene, 264.3 g (6 mol) of acetaldehyde, 32.6 g (0.2 mol) of N-hydroxyphthalimide (NHPI), and 484 g (2 mol) of benzoyl peroxide (BPO) were added sequentially. The mixture was stirred and heated to 75 °C under reflux for 6 h. After the reaction was complete, the toluene solvent was removed by distillation. The residue was purified twice by recrystallization with ethanol to obtain 279.68 g (1.84 mol) of 2,4-dihydroxyacetophenone, which was a white needle-like crystal with a yield of 92%, a purity greater than 99.5%, a melting point of 143–145 °C, and a molecular weight of 152.
[0037] The proton NMR spectrum is as follows: Figure 1 As shown, 1 H NMR (400 MHz, CDCl3) δ = 12.71 (s, 1H), 7.66 (d, J = 8.5 Hz, 1H), 6.47 – 6.37 (m, 2H), 2.59 (s, 3H).
[0038] Infrared such as Figure 2 As shown, 3293.84 cm -1 The nearby broad and strong absorption peak is the stretching vibration absorption peak of the phenolic hydroxyl group (-OH), corresponding to the association structure of two phenolic hydroxyl groups in the molecule, indicating the presence of a phenolic hydroxyl functional group in the product. 2997.36 cm⁻¹ -1 The absorption peak at 1628.55 cm⁻¹ is a characteristic peak of the CH stretching vibration of the methyl group (-CH₃) in the acetyl group, indicating the presence of an acetyl group in the molecule. -1 With 1603.04 cm -1 The strong absorption peaks at these locations are attributed to the C=C stretching vibrations of the aromatic ring skeleton and the stretching vibrations of the ketone carbonyl group (C=O) conjugated with the phenolic hydroxyl group, respectively. Due to the influence of intramolecular hydrogen bonding and conjugation effects, the wavenumber of the ketone carbonyl absorption peak is lower than that of saturated ketones, consistent with the structural characteristics of 2,4-dihydroxyacetophenone. (1500–1000 cm⁻¹) -1 Multiple characteristic absorption peaks in the range (e.g., 1496.46 cm⁻¹) -1 1419.85 cm -1 1372.22 cm -1 1279.56 cm -1 1200.69 cm -1These correspond to the aromatic ring skeleton vibration, the CO stretching vibration of the phenolic hydroxyl group, and the CH bending vibration of the methyl group, respectively, which are consistent with the benzene ring substitution and phenolic ketone structural characteristics of the target molecule. Fingerprint region (1000–400 cm⁻¹) -1 Characteristic absorption peaks (e.g., 821.97 cm⁻¹) -1 751.79 cm -1 658.07 cm -1 The peak positions and shapes of the peaks (etc.) are out-of-plane bending vibrations of the aromatic ring CH, which are consistent with the characteristics of 1,2,4-trisubstituted benzene rings, further confirming the substitution mode of the target molecule.
[0039] Example 2
[0040] The difference from Example 1 is that the reaction temperature is 65°C, and the specific process is as follows:
[0041] To a 2500 mL round-bottom flask equipped with a reflux condenser, 220.2 g (2 mol) of resorcinol, 1500 mL of toluene, 264.3 g (6 mol) of acetaldehyde, 32.6 g (0.2 mol) of N-hydroxyphthalimide (NHPI), and 484 g (2 mol) of benzoyl peroxide (BPO) were added sequentially. The mixture was stirred and heated to 65 °C under reflux for 6 h. After the reaction was complete, the toluene solvent was removed by distillation, and the residue was purified twice by recrystallization with ethanol to give 146.1 g (0.96 mol) of 2,4-dihydroxyacetophenone as a white solid, with a yield of 48%.
[0042] Example 3
[0043] The difference from Example 1 is that the reaction temperature was 95°C, while all other aspects were the same as in Example 1. The yield was 52%. The inventors believe that the reason for this is that if the temperature is too high, acetaldehyde will volatilize excessively, which is not conducive to the forward reaction and will also exacerbate side reactions, resulting in a lower yield.
[0044] Example 4
[0045] The difference from Example 1 is that the equivalent ratio of acetaldehyde to resorcinol is 2:1, and the specific process is as follows:
[0046] To a 2500 mL round-bottom flask equipped with a reflux condenser, 220.2 g (2 mol) of resorcinol, 1500 mL of toluene, 176.2 g (4 mol) of acetaldehyde, 32.6 g (0.2 mol) of N-hydroxyphthalimide (NHPI), and 484 g (2 mol) of benzoyl peroxide (BPO) were added sequentially. The mixture was stirred and heated to 75 °C under reflux for 6 h. After the reaction was complete, the toluene solvent was removed by distillation, and the residue was purified twice by recrystallization with ethanol as the solvent to obtain 170.4 g (1.12 mol) of 2,4-dihydroxyacetophenone as a white solid, with a yield of 56%.
[0047] Example 5
[0048] The difference from Example 1 is that the acetaldehyde and resorcinol equivalent ratio is 4:1, with 352.4 g (8 mol) of acetaldehyde, and the rest are the same as in Example 1. The yield is 64%.
[0049] Example 6
[0050] The difference from Example 1 is that the molar amount of NHPI is 1% of the molar amount of resorcinol, and the specific process is as follows:
[0051] To a 2500 mL round-bottom flask equipped with a reflux condenser, 220.2 g (2 mol) of resorcinol, 1500 mL of toluene, 264.3 g (6 mol) of acetaldehyde, 3.26 g (0.02 mol) of N-hydroxyphthalimide (NHPI), and 484 g (2 mol) of benzoyl peroxide (BPO) were added sequentially. The mixture was stirred and heated to 75 °C under reflux for 6 h. After the reaction was complete, the toluene solvent was removed by distillation, and the residue was purified twice by recrystallization with ethanol as the solvent to obtain 185.6 g (1.22 mol) of 2,4-dihydroxyacetophenone as a white solid, with a yield of 61%.
[0052] Example 7
[0053] The difference from Example 1 is that the molar amount of NHPI is 20% of the molar amount of resorcinol, with 65.2 g (0.4 mol) of NHPI, and the rest is the same as in Example 1. The yield is 70%. Increasing the amount of catalyst increases the cost and decreases the yield.
[0054] Example 8
[0055] The difference from Example 1 is that the molar amount of BPO is 5% of the molar amount of resorcinol, and the specific process is as follows:
[0056] To a 2500 mL round-bottom flask equipped with a reflux condenser, 220.2 g (2 mol) of resorcinol, 1500 mL of toluene, 264.3 g (6 mol) of acetaldehyde, 32.6 g (0.2 mol) of N-hydroxyphthalimide (NHPI), and 24.2 g (0.1 mol) of benzoyl peroxide were added sequentially. The mixture was stirred and heated to 75 °C under reflux for 6 h. After the reaction was complete, the toluene solvent was removed by distillation. The residue was purified twice by recrystallization using ethanol as the solvent to obtain 115.6 g (0.76 mol) of 2,4-dihydroxyacetophenone as a white solid, with a yield of 38%.
[0057] Example 9
[0058] The difference from Example 1 is that the molar amount of BPO is 10% of the molar amount of resorcinol, and the specific process is as follows:
[0059] To a 2500 mL round-bottom flask equipped with a reflux condenser, 220.2 g (2 mol) of resorcinol, 1500 mL of toluene, 264.3 g (6 mol) of acetaldehyde, 32.6 g (0.2 mol) of N-hydroxyphthalimide (NHPI), and 48.4 g (0.2 mol) of benzoyl peroxide were added sequentially. The mixture was stirred and heated to 75 °C under reflux for 6 h. After the reaction was complete, the toluene solvent was removed by distillation, and the residue was purified twice by recrystallization with ethanol to give 197.8 g (1.3 mol) of 2,4-dihydroxyacetophenone as a white solid, with a yield of 65%.
[0060] Example 10
[0061] The difference from Example 1 is that the molar amount of BPO is 120% of the molar amount of resorcinol, with 580.8 g (2.4 mol) of BPO, and the rest are the same as in Example 1. The yield is 75%.
[0062] Example 11
[0063] Unlike Example 9, BPO was added dropwise to the reaction system in solution form, as follows:
[0064] To a 2500 mL round-bottom flask equipped with a reflux condenser, 220.2 g (2 mol) of resorcinol, 1000 mL of toluene, 264.3 g (6 mol) of acetaldehyde, and 32.6 g (0.2 mol) of N-hydroxyphthalimide were added sequentially, and the mixture was stirred and heated to 75 °C. Separately, in a 1000 mL beaker, 48.4 g (0.2 mol) of benzoyl peroxide was dissolved in 500 mL of toluene. The resulting benzoyl peroxide toluene solution was continuously added dropwise to the above reaction system using a syringe pump until the reaction was complete. The system was refluxed and stirred for a total of 6 h. After the reaction was complete, the toluene solvent was removed by distillation. The residue was purified twice by recrystallization using ethanol as the solvent to obtain 216.1 g (1.42 mol) of 2,4-dihydroxyacetophenone as a white solid, with a yield of 71%.
[0065] Example 12
[0066] The difference from Example 1 is that the solvent toluene is replaced with chlorobenzene, and the specific process is as follows:
[0067] To a 2500 mL round-bottom flask equipped with a reflux condenser, 220.2 g (2 mol) of resorcinol, 1500 mL of chlorobenzene, 264.3 g (6 mol) of acetaldehyde, 32.6 g (0.2 mol) of N-hydroxyphthalimide (NHPI), and 484 g (2 mol) of benzoyl peroxide (BPO) were added sequentially. The mixture was stirred and heated to 75 °C under reflux for 16 h. After the reaction was complete, the chlorobenzene solvent was removed by distillation, and the residue was purified twice by recrystallization with ethanol as the solvent to obtain 203.9 g (1.34 mol) of 2,4-dihydroxyacetophenone as a white solid, with a yield of 67%.
[0068] Example 13
[0069] The difference from Example 1 is that the solvent toluene was replaced with cyclohexane; otherwise, the process was the same as in Example 1. Yield: 10%.
[0070] Note: The spectra of the target products obtained in Examples 2-13 are not substantially different from those in Example 1. In order to reduce repetition and shorten the length, they will not be provided again.
Claims
1. A method for preparing 2,4-dihydroxyacetophenone using acetaldehyde as the acetyl source, characterized in that: In the presence of an oxidant and a catalyst, acetaldehyde is used as the acetyl source and reacts directly with resorcinol via free radical acylation to yield 2,4-dihydroxyacetophenone. No transition metal salts are required during the reaction.
2. The method for preparing 2,4-dihydroxyacetophenone using acetaldehyde as the acetyl source according to claim 1, characterized in that: The oxidant is benzoyl peroxide; the catalyst is N-hydroxyphthalimide.
3. The method for preparing 2,4-dihydroxyacetophenone using acetaldehyde as the acetyl source according to claim 1 or 2, characterized in that: The molar ratio of oxidant to resorcinol is (0.1~2):
2.
4. The method for preparing 2,4-dihydroxyacetophenone using acetaldehyde as the acetyl source according to claim 1 or 2, characterized in that: The molar ratio of catalyst to resorcinol is (0.15~0.25):
2.
5. The method for preparing 2,4-dihydroxyacetophenone using acetaldehyde as the acetyl source according to claim 1 or 2, characterized in that: The molar ratio of acetaldehyde to resorcinol is (4~6):
2.
6. The method for preparing 2,4-dihydroxyacetophenone using acetaldehyde as the acetyl source according to claim 1 or 2, characterized in that: The reaction temperature is 65~85℃, and the reaction time is 4-6h.
7. The method for preparing 2,4-dihydroxyacetophenone using acetaldehyde as the acetyl source according to claim 1 or 2, characterized in that: The reaction is carried out in a solvent, such as toluene or chlorobenzene.
8. The method for preparing 2,4-dihydroxyacetophenone using acetaldehyde as the acetyl source according to claim 1, characterized in that: Resorcinol, acetaldehyde, N-hydroxyphthalimide and benzoyl peroxide were added to an organic solvent and refluxed at 65-85°C for 4-6 hours. After the reaction was completed, the mixture was cooled, separated and purified to obtain 2,4-dihydroxyacetophenone.
9. The method for preparing 2,4-dihydroxyacetophenone using acetaldehyde as the acetyl source according to claim 1, characterized in that: Includes the following steps: 1) Add resorcinol, acetaldehyde and N-hydroxyphthalimide to an organic solvent and heat to 65~85℃; 2) Dissolve benzoyl peroxide in a solvent and add it dropwise to the reaction solution obtained in step 1). Reflux the reaction at 65~85℃ for 4-6 hours. After the reaction is completed, cool the solution, separate and purify it to obtain 2,4-dihydroxyacetophenone.
10. The method for preparing 2,4-dihydroxyacetophenone using acetaldehyde as the acetyl source according to claim 8 or 9, characterized in that: The solvent was removed by distillation and the product was recrystallized 1-3 times with ethanol to obtain 2,4-dihydroxyacetophenone.