Method for preparing p-hydroxyanisole with high selectivity
By using a combination of anisole, TS-1 molecular sieve, and hydrogen peroxide, along with temperature gradient and batch feeding, the problems of poor selectivity and difficult wastewater treatment of p-hydroxyanisole in existing technologies have been solved, achieving highly selective synthesis and effective resource recovery.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2026-03-06
- Publication Date
- 2026-04-07
AI Technical Summary
Existing technologies for preparing p-hydroxyanisole suffer from problems such as poor raw material selectivity, harsh reaction conditions, high costs, and difficulties in wastewater treatment.
Using anisole as raw material, TS-1 molecular sieve as catalyst, and hydrogen peroxide as oxidant, a highly selective synthesis of p-hydroxyanisole was achieved by combining extraction and distillation processes with temperature gradient control and batch feeding. Unconverted raw materials and catalysts were also recovered.
This method enables highly selective synthesis of p-hydroxyanisole, improving product purity and yield while reducing waste of raw materials and catalysts and minimizing wastewater generation.
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Figure CN121800622A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of pharmaceutical intermediates, and more particularly to a method for the highly selective preparation of p-hydroxyanisole. Background Technology
[0002] p-Hydroxyanisole is an important fine chemical product with wide applications in pharmaceuticals, pesticides, and fragrances. According to literature, the synthesis of p-hydroxyanisole can be divided into three types depending on the raw materials. The first type uses p-diphenol as a methylating agent, with dimethyl sulfate as the methylating agent, but this method is highly toxic. Alternatively, it involves the reaction of diphenol and methanol, but this method has poor selectivity and easily forms diether compounds that are difficult to separate from the product. The second type uses p-aminoanisole as a raw material, and obtains p-hydroxyanisole through a two-step reaction of diazotization and hydrolysis under the action of mixed acids. However, aminoanisole is highly toxic, and the reaction conditions are harsh. The third type uses anisole as a raw material to synthesize p-hydroxyanisole. The synthesis process (CN113443970A) uses rhodium dimer acetate, diethyl iodophenyl ester, trifluoroacetic anhydride, and other organic reagents, resulting in high costs and the generation of large amounts of wastewater. Yan Huapeng (Yan Huapeng, Huang Pengming, Yang Ying, et al. Green synthesis of hydroxyanisole using nano-TS-1 molecular sieve and hydrogen peroxide [J]. Journal of Jiangxi Normal University (Natural Science Edition), 2024, 48(5):479-484.) synthesized hydroxyanisole using anisole as raw material and hydrogen peroxide catalyzed by H-TS-1 molecular sieve. The yield of the mixture of ortho and para positions was 31%, and the selectivity was 0.43:1 for p-hydroxyanisole and ortho-hydroxyanisole. The selectivity for p-hydroxyanisole was poor. The raw material conversion rate was 31.15%. No method for separating the remaining raw material was given. Summary of the Invention
[0003] The purpose of this invention is to provide a highly selective method for preparing p-hydroxyanisole, thereby solving the aforementioned problems in the prior art.
[0004] To achieve the above-mentioned objectives, the present invention provides the following technical solution: This invention provides a method for highly selectively preparing p-hydroxyanisole, comprising the following steps: (1) Mix anisole and TS-1 molecular sieve and heat to the first temperature, then add the first hydrogen peroxide to carry out the first stage reaction; after the first stage reaction is completed, heat to the second temperature and add the second hydrogen peroxide to carry out the second stage reaction. (2) After the second stage reaction is completed, the obtained reaction solution is cooled to room temperature and filtered under reduced pressure to obtain filtrate and TS-1 molecular sieve; the TS-1 molecular sieve is washed and recovered with water. (3) Separate the filtrate to obtain a first organic phase and a first aqueous phase; extract the first aqueous phase with a first organic solvent to obtain a second aqueous phase and a second organic phase; combine the second organic phase with the first organic phase to obtain a composite organic phase; extract the composite organic phase with alkali to obtain a third aqueous phase and a third organic phase; (4) Combine the second aqueous phase and the third aqueous phase, adjust the pH to acidic using acid to obtain a composite aqueous phase, extract the composite aqueous phase using a second organic solvent to obtain a fourth organic phase; distill the fourth organic phase under reduced pressure to obtain p-hydroxyanisole.
[0005] Preferably, the mass ratio of anisole to TS-1 molecular sieve is 3.5~5.5:1~2.
[0006] Preferably, the total amount of the first hydrogen peroxide and the second hydrogen peroxide, and the amount of anisole, are in a ratio of 0.3 to 1:1.
[0007] Preferably, the mass fraction of the first hydrogen peroxide and the second hydrogen peroxide is 5% to 30% independently.
[0008] Preferably, taking the total mass of the first hydrogen peroxide and the second hydrogen peroxide as 1, the mass of the first hydrogen peroxide accounts for 20-80% of the total mass.
[0009] Preferably, the temperature of the first stage reaction is 40~100℃; the reaction time of the first stage reaction is 0.5~1h.
[0010] Preferably, the temperature of the second stage reaction is 60~120℃; the reaction time of the second stage reaction is 2~4h.
[0011] Preferably, the first organic solvent and the second organic solvent are independently one or more of dichloromethane, ethyl acetate, petroleum ether, diethyl ether, and n-hexane.
[0012] Preferably, the alkali is one of sodium carbonate solution, sodium bicarbonate solution, triethylamine, and sodium hydroxide solution.
[0013] Preferably, the acid is one of acetic acid, hydrochloric acid, or sulfuric acid.
[0014] As can be seen from the above technical solution, compared with the prior art, the present invention has the following beneficial effects: This invention uses anisole as raw material, TS-1 molecular sieve as catalyst, hydrogen peroxide as oxidant, and water as solvent. By changing the temperature gradient and feeding in batches, p-hydroxyanisole is synthesized with high selectivity. The unconverted anisole and catalyst are recovered and reused through a separation process. Attached Figure Description
[0015] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below.
[0016] Figure 1 This is a schematic diagram of the synthesis process of p-hydroxyanisole according to the present invention. Detailed Implementation
[0017] This invention provides a method for the highly selective preparation of p-hydroxyanisole, the synthetic process of which is shown in the schematic diagram below. Figure 1 As shown, it includes the following steps: (1) Mix anisole and TS-1 molecular sieve and heat to the first temperature, then add the first hydrogen peroxide to carry out the first stage reaction; after the first stage reaction is completed, heat to the second temperature and add the second hydrogen peroxide to carry out the second stage reaction. (2) After the second stage reaction is completed, the obtained reaction solution is cooled to room temperature and filtered under reduced pressure to obtain filtrate and TS-1 molecular sieve; the TS-1 molecular sieve is washed and recovered with water. (3) Separate the filtrate to obtain a first organic phase and a first aqueous phase; extract the first aqueous phase with a first organic solvent to obtain a second aqueous phase and a second organic phase; combine the second organic phase with the first organic phase to obtain a composite organic phase; extract the composite organic phase with alkali to obtain a third aqueous phase and a third organic phase; (4) Combine the second aqueous phase and the third aqueous phase, adjust the pH to acidic using acid to obtain a composite aqueous phase, extract the composite aqueous phase using a second organic solvent to obtain a fourth organic phase; distill the fourth organic phase under reduced pressure to obtain p-hydroxyanisole.
[0018] In this invention, the TS-1 molecular sieve is a commercially available product, purchased from Zhongchumei New Materials Co., Ltd. (NOV034 TS-1), Jiangsu Xianfeng Nanomaterials Technology Co., Ltd. (TS-1), or Zhuoyue Environmental New Materials (Shanghai) Co., Ltd. (ZY-TS-2308).
[0019] In this invention, the mass ratio of anisole to TS-1 molecular sieve is preferably 3.5~5.5:1~2, more preferably 4~5.5:1, and even more preferably 5:1.
[0020] In this invention, the ratio of the total amount of the first hydrogen peroxide and the second hydrogen peroxide to the amount of anisole is preferably 0.3 to 1:1, more preferably 0.5 to 1:1, and even more preferably 1:1.
[0021] In this invention, the mass fraction of the first hydrogen peroxide and the second hydrogen peroxide is preferably 5-30%, more preferably 10-20%, and even more preferably 15%.
[0022] In this invention, taking the total mass of the first hydrogen peroxide and the second hydrogen peroxide as 1, the mass of the first hydrogen peroxide preferably accounts for 20-80% of the total mass, more preferably 40-70%, and even more preferably 67%.
[0023] In this invention, the temperature of the first stage reaction is preferably 40~100℃, more preferably 50~80℃, and even more preferably 60℃; the reaction time of the first stage reaction is preferably 0.5~1h, and even more preferably 0.5h.
[0024] In this invention, the temperature of the second stage reaction is preferably 60~120℃, more preferably 65~100℃, and even more preferably 70℃; the reaction time of the second stage reaction is preferably 2~4h, and even more preferably 3h.
[0025] In this invention, the first organic solvent is preferably one or more of dichloromethane, ethyl acetate, petroleum ether, diethyl ether, and n-hexane, more preferably dichloromethane or ethyl acetate, and even more preferably dichloromethane.
[0026] In this invention, the second organic solvent is preferably one or more of dichloromethane, ethyl acetate, petroleum ether, diethyl ether, and n-hexane, more preferably dichloromethane or ethyl acetate, and even more preferably dichloromethane.
[0027] In this invention, the alkali is preferably one of sodium carbonate solution, sodium bicarbonate solution, triethylamine, and sodium hydroxide solution, more preferably sodium hydroxide solution, and even more preferably a 10% sodium hydroxide aqueous solution by mass.
[0028] In this invention, the acid is preferably one of acetic acid, hydrochloric acid, and sulfuric acid, more preferably hydrochloric acid, and even more preferably 5% dilute hydrochloric acid by mass fraction.
[0029] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.
[0030] Example 1
[0031] This embodiment provides a method for highly selectively preparing p-hydroxyanisole, comprising the following steps: Add 50g of anisole and 10g of TS-1 molecular sieve (NOV034 TS-1 from Zhongshunmei New Materials Co., Ltd.) to a 250mL four-necked flask and stir mechanically until homogeneous. During stirring, raise the temperature to 60℃. Slowly add 42g of 15% hydrogen peroxide dropwise to the four-necked flask, completing the addition over approximately 30 minutes. After the addition is complete, maintain the temperature for 30 minutes, then raise the temperature to 70℃ and add 21g of 15% hydrogen peroxide dropwise while stirring.
[0032] After stirring for 3 hours, the reaction was stopped. The reaction solution was cooled to room temperature, poured into a sintered glass funnel, and filtered under reduced pressure to obtain the catalyst and filtrate. The catalyst in the sintered glass funnel was rinsed with 80 mL of water and recycled. The filtrate was separated to obtain a first organic phase and a first aqueous phase. The first aqueous phase was extracted with dichloromethane to obtain a second aqueous phase and a second organic phase (dichloromethane layer). The second organic phase was combined with the first organic phase and extracted with 10% sodium hydroxide aqueous solution to obtain a third aqueous phase and a third organic phase. HPLC analysis showed no product in the third organic phase. The third organic phase was then distilled under reduced pressure to remove dichloromethane and stored (this is the remaining anisole). The second and third aqueous phases were combined, and the pH was adjusted to 4.5 with 5% dilute hydrochloric acid. The acidic aqueous phase was extracted with dichloromethane, and the extraction endpoint was detected by HPLC. The organic phases were combined, and dichloromethane was removed under reduced pressure to obtain a brownish-black liquid, which is the crude product. The ratio of p-hydroxyanisole to o-hydroxyanisole in the crude product was 9:1, with a yield of 40% and a conversion rate of 40%.
[0033] Comparative Example 1
[0034] Add 50g of anisole and 10g of TS-1 molecular sieve (NOV034 TS-1, Zhongchumei New Materials Co., Ltd.) to a 250mL four-necked flask and stir mechanically until homogeneous. During stirring, raise the temperature to 70℃. Slowly add 63g of 15% hydrogen peroxide to the four-necked flask, completing the addition over approximately 40 minutes. After the addition is complete, stir the reaction for 3 hours. The post-processing method is the same as in Example 1. The crude product has a p-hydroxyanisole:o-hydroxyanisole ratio of 1:1, with a yield of 34% and a conversion rate of 35%.
[0035] Comparative Example 2
[0036] Add 50g of anisole and 10g of TS-1 molecular sieve (NOV034 TS-1 from Zhongshunmei New Materials Co., Ltd.) to a 250mL four-necked flask and stir mechanically until homogeneous. During stirring, raise the temperature to 60℃. Slowly add 63g of 15% hydrogen peroxide dropwise to the four-necked flask, completing the addition over approximately 40 minutes. After the addition is complete, maintain the temperature for 30 minutes, then raise the temperature to 70℃ and stir for 3 hours. The post-processing method is the same as in Example 1. The crude product has a p-hydroxyanisole:o-hydroxyanisole ratio of 2:1, a yield of 28%, and a conversion rate of 30%.
[0037] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.
Claims
1. A method for highly selectively preparing p-hydroxyanisole, characterized in that, Includes the following steps: (1) Mix anisole and TS-1 molecular sieve and heat to the first temperature, then add the first hydrogen peroxide to carry out the first stage reaction; after the first stage reaction is completed, heat to the second temperature and add the second hydrogen peroxide to carry out the second stage reaction. (2) After the second stage reaction is completed, the obtained reaction solution is cooled to room temperature and filtered under reduced pressure to obtain filtrate and TS-1 molecular sieve; the TS-1 molecular sieve is washed and recovered with water. (3) Separate the filtrate to obtain a first organic phase and a first aqueous phase; extract the first aqueous phase with a first organic solvent to obtain a second aqueous phase and a second organic phase; combine the second organic phase with the first organic phase to obtain a composite organic phase; extract the composite organic phase with alkali to obtain a third aqueous phase and a third organic phase; (4) Combine the second aqueous phase and the third aqueous phase, adjust the pH to acidic using acid to obtain a composite aqueous phase, extract the composite aqueous phase using a second organic solvent to obtain a fourth organic phase; distill the fourth organic phase under reduced pressure to obtain p-hydroxyanisole.
2. The method for highly selectively preparing p-hydroxyanisole according to claim 1, characterized in that, The mass ratio of anisole to TS-1 molecular sieve is 3.5~5.5:1~2.
3. The method for highly selectively preparing p-hydroxyanisole according to claim 1, characterized in that, The total amount of the first hydrogen peroxide and the second hydrogen peroxide, and the amount of anisole, are in a ratio of 0.3 to 1:
1.
4. The method for highly selectively preparing p-hydroxyanisole according to claim 1, characterized in that, The mass fractions of the first and second hydrogen peroxide solutions are independently 5% to 30%.
5. The method for highly selectively preparing p-hydroxyanisole according to claim 1, characterized in that, Taking the total mass of the first hydrogen peroxide and the second hydrogen peroxide as 1, the mass of the first hydrogen peroxide accounts for 20-80% of the total mass.
6. The method for highly selectively preparing p-hydroxyanisole according to claim 1, characterized in that, The temperature of the first stage reaction is 40~100℃; the reaction time of the first stage reaction is 0.5~1h.
7. The method for highly selectively preparing p-hydroxyanisole according to claim 1, characterized in that, The temperature of the second stage reaction is 60~120℃; the reaction time of the second stage reaction is 2~4h.
8. The method for highly selectively preparing p-hydroxyanisole according to claim 1, characterized in that, The first organic solvent and the second organic solvent are independently one or more of dichloromethane, ethyl acetate, petroleum ether, diethyl ether, and n-hexane.
9. The method for highly selectively preparing p-hydroxyanisole according to claim 1, characterized in that, The alkali is one of sodium carbonate solution, sodium bicarbonate solution, triethylamine, and sodium hydroxide solution.
10. The method for highly selectively preparing p-hydroxyanisole according to claim 1, characterized in that, The acid is one of acetic acid, hydrochloric acid, or sulfuric acid.