Deprotection method of p-tert-butoxyphenethyl methyl ether

Abstract

The invention belongs to the field of fine chemical engineering, and discloses a deprotection method of p-tert-butoxyphenethyl methyl ether, which comprises the following steps: under the action of a solid acid catalyst, heating p-tert-butoxyphenethyl methyl ether for deprotection reaction to obtain p-(2-methoxy) ethyl phenol; the solid acid catalyst comprises aluminum phosphate and an alkaline metal oxide modified on the aluminum phosphate, and the alkaline metal oxide contains one or more metal elements of K, Ca, Na, Ba or Mg. The method has the advantages of less discharge of three wastes, low operation cost and high production efficiency, is used for continuous production of p-(2-methoxy) ethyl phenol, and can adopt higher temperature and higher air speed.

Description

Technical Field

[0001] The invention belongs to the technical field of fine chemicals and relates to a deprotection method for p-tert-butoxyphenethyl methyl ether. Background Art

[0002] Using a protecting agent such as isobutylene to initially protect certain active functional groups in the reactants, followed by a deprotection reaction as the final step, is a common practice in the synthetic field. Currently, the fine chemical industry primarily uses liquid acids as catalysts for deprotection (tert-butyl) reactions. Liquid acid catalysts offer advantages such as high catalytic activity and low cost, but they require neutralization and water washing after the reaction, resulting in high levels of waste gas and complex processes. Solid acid catalysts, with their advantages of easy separation and reduced waste gas, are widely used in the petrochemical industry. Petrochemical products, due to their small molecular weight and low boiling point, are easily vaporized, and therefore typically undergo gas-solid phase reactions. Fine chemical products, on the other hand, have larger molecular weights and high boiling points, making them difficult to vaporize and typically require liquid phase reactions. Therefore, conventional solid acid catalysts used in the petrochemical industry are often unsuitable for use in the fine chemical industry.

[0003] Patent CN106955687B discloses a catalyst for the cracking of tert-amyl methyl ether to produce isopentene. This invention uses sulfate- and fluoride-modified alumina as a catalyst. At a reaction temperature of 160°C, the conversion rate and selectivity reach over 95%. Although this catalyst exhibits high catalytic activity, the sulfate and fluoride ions are easily lost, making it suitable only for gas-solid phase reactions. For liquid phase reactions, sulfate and fluoride ions are easily lost, resulting in decreased catalyst activity and corrosion of reactor equipment. Fine chemical products have large molecular weights and high boiling points, making their molecular structures unstable at high temperatures. Liquid phase reactions are typically used, necessitating the development of solid acid catalysts suitable for these reactions.

[0004] Patent CN111530379A discloses a process for cracking methyl tert-butyl ether to produce isobutylene, using a sulfonic acid resin as a catalyst. Sulfonic acid resin catalysts have strong acidity and catalytic activity, but they suffer from poor high-temperature resistance. When the reaction temperature exceeds 120°C, the active components readily decompose and fall off. Sulfonic acid resins also have poor high-temperature resistance, so after deactivation, they cannot be regenerated through high-temperature calcination to restore their catalytic activity. These drawbacks, such as poor high-temperature resistance and the inability to regenerate after deactivation, limit their application in the fine chemical industry.

[0005] Patent CN100482629C discloses a method for synthesizing p-(2-methoxy)ethylphenol. The final step, the deprotection reaction of p-tert-butoxyphenethyl methyl ether, uses a liquid acid (sulfuric acid, hydrochloric acid, phosphoric acid, or nitric acid) as a catalyst to catalyze the deprotection reaction. This method achieves high reactant conversion and product selectivity, but produces large amounts of wastewater and waste acid, and requires the use of a reactor made of specialized materials to avoid equipment corrosion.

[0006] Patent CN109651094B discloses a method for preparing p-(2-methoxy)ethylphenol. In the final step, p-tert-butoxyphenethyl methyl ether undergoes a deprotection reaction in the presence of a catalyst, thionyl chloride. This method achieves high reactant conversion and product selectivity, but thionyl chloride is highly toxic, producing large amounts of toxic and hazardous substances and being environmentally unfriendly.

[0007] Patent CN116020438B discloses a solid acid catalyst supported by γ-alumina modified with an acidic metal oxide. This catalyst exhibits good performance in the deprotection reaction of tert-butoxyphenethyl methyl ether, with product selectivity exceeding 98%. Furthermore, the catalyst is highly stable and has not been deactivated after 200 hours of continuous reaction. However, this technology still has some limitations. For example, the catalyst preparation conditions are relatively complex, and a transition metal needs to be impregnated twice to achieve a more ideal selectivity, which increases the cost of the catalyst. Furthermore, under certain specific operating conditions, it may not fully meet the efficiency and economy requirements of industrial production. For example, at a liquid space velocity of 1 h -1 Under certain conditions, the conversion rate cannot exceed 80%, especially the catalyst is not suitable for reactions at high temperatures. At the same time, when reacting at temperatures above 190°C, although a higher liquid space velocity can be used, carbon will accumulate on the catalyst surface, causing the catalyst to be deactivated, thereby significantly reducing the selectivity and affecting the stability of the continuous reaction at high temperatures.

[0008] In summary, the catalysts currently used in deprotection reactions in the fine chemical industry are primarily liquid acids, generating large amounts of waste acid, wastewater, and toxic and hazardous substances. Furthermore, the deprotection reaction in the synthesis of p-(2-methoxy)ethylphenol is often performed in batches, resulting in long production cycles, unstable product quality, and difficulties in achieving flexible production. Furthermore, the solid acid catalysts commonly used in the petrochemical industry are not suitable for the production of fine chemicals. Therefore, there is an urgent need to develop solid acid catalysts and continuous deprotection reaction processes suitable for fine chemical production. Summary of the Invention

[0009] The present invention aims to provide a deprotection method for p-tert-butoxyphenethyl methyl ether to address the environmental concerns and inefficiency associated with using a liquid acid as a catalyst for the deprotection reaction, as well as the discontinuous process. It also addresses the complex preparation, high cost, high-temperature resistance, and low conversion rates of existing solid acid catalysts. The present invention utilizes a solid acid catalyst in place of a liquid acid catalyst to catalyze the deprotection reaction of p-tert-butoxyphenethyl methyl ether, resulting in reduced discharge of three wastes. Furthermore, the method, combined with a fixed-bed reactor, enables continuous production of the p-tert-butoxyphenethyl methyl ether deprotection reaction, making it suitable for the continuous production of p-(2-methoxy)ethylphenol.

[0010] The technical solutions of the present invention are as follows: A deprotection method for p-tert-butoxyphenethyl methyl ether comprises: heating the p-tert-butoxyphenethyl methyl ether under the action of a solid acid catalyst to carry out a deprotection reaction to obtain p-(2-methoxy)ethylphenol; The solid acid catalyst includes aluminum phosphate and an alkaline metal oxide modified on the aluminum phosphate. The metal elements contained in the alkaline metal oxide include one or more of K, Ca, Na, Ba or Mg.

[0011] In the present invention, the loading amount of the alkaline metal oxides such as K, Ca, Na, Ba, Mg, etc. is 1 to 5 wt% (calculated as the alkali metal element).

[0012] Preferably, the alkaline oxide-modified aluminum phosphate solid acid catalyst is prepared by an impregnation method, and the specific steps are as follows: The solid acid catalyst is obtained by heating an aqueous solution containing one or more nitrates of K, Ca, Na, Ba, and Mg, adding aluminum phosphate, modifying the solution by an impregnation method, and drying and calcining the solution.

[0013] Preferably, during the preparation of the solid acid catalyst, the heating temperature is 40-60° C. and the immersion time is 20-40 minutes.

[0014] Preferably, during the preparation of the solid acid catalyst, the drying temperature is 100-120° C., and the drying time is 10-14 hours; the calcination temperature is 350-450° C., and the calcination time is 3-7 hours.

[0015] Aluminum phosphate is the most common catalyst support in industry. It is inexpensive, highly thermally stable, and has strong acidity, possessing both L and B acidity. Basic oxides such as K, Ca, Na, Ba, and Mg possess strong basicity. Modifying aluminum phosphate with basic oxides can appropriately reduce the catalyst's acidity, improving product selectivity and inhibiting side reactions such as coking, thereby extending catalyst life. p-(2-methoxy)ethylphenol is a key intermediate in the synthesis of the drug metoprolol. The final step in its synthesis involves the deprotection of p-tert-butoxyphenethyl methyl ether under acid-catalyzed conditions to yield the target product, p-(2-methoxy)ethylphenol. The inventors discovered that the deprotection of p-tert-butoxyphenethyl methyl ether can be catalyzed by a solid acid aluminum phosphate catalyst modified with a basic metal oxide at atmospheric pressure, achieving high conversion and selectivity.

[0016] The performance of the solid acid catalyst prepared using the above method was evaluated by loading a catalyst with a diameter of 1.2-1.5 mm into a stainless steel fixed-bed reactor with an inner diameter of 15 mm. The heating furnace was started, and after the catalyst bed temperature reached the set temperature, a plunger pump was activated to control the feed rate of the reactant, p-tert-butyloxyphenethyl methyl ether. After passing through the catalyst bed of the fixed-bed reactor, the reaction liquid entered a gas-liquid separator, where the liquid product was collected and the gaseous product (isobutylene) was discharged. The liquid product was quantitatively analyzed using a gas chromatograph, and the conversion and selectivity were calculated.

[0017] Preferably, the reaction is carried out in a continuous manner, wherein the solid acid catalyst is filled in a fixed-bed continuous reactor, and then p-tert-butoxyphenethyl methyl ether is introduced into the fixed-bed continuous reactor for deprotection reaction.

[0018] As a further preference, the reaction temperature is 210-250°C, the liquid space velocity is 1-2h -1 The catalyst of the present invention can withstand higher temperatures and higher space velocities and is more convenient for industrial use.

[0019] Compared with the prior art, the present invention has the following beneficial effects: (1) The present invention adopts a solid acid catalyst to replace a liquid acid catalyst to catalyze the deprotection reaction, which reduces the discharge of three wastes. In combination with a fixed bed reactor, the deprotection reaction can be continuously operated. Moreover, it is a gas phase reaction, the process is simple, and it is easy to achieve industrial scale-up, which is suitable for the production of large-tonnage chemical products.

[0020] (2) The present invention uses a solid acid catalyst in combination with a fixed-bed continuous reactor to catalyze the deprotection reaction of p-tert-butoxyphenethyl methyl ether, with a maximum selectivity of over 98%. It has the advantages of simple operation and continuous production, and is also in line with the future development direction of green, continuous and intelligent fine chemical industry.

[0021] (3) Compared with the complex impregnation, drying, and calcination conditions used in the prior art, the solid acid catalyst used in the present invention has a simpler preparation process, lowers equipment requirements, and uses readily available and inexpensive raw materials, making it suitable for large-scale industrial production. Furthermore, the combination of basic metal oxide-modified aluminum phosphate exhibits a unique synergistic effect in catalyst performance, resulting in improved stability and adaptability to higher temperatures and space velocities, further enhancing the catalyst's overall performance.

[0022] (4) The catalyst of the present invention not only performs comparable to existing technologies but also offers advantages in terms of preparation cost and operational complexity. By optimizing the catalyst composition and preparation process, the present invention can significantly reduce production costs and improve production efficiency in practical applications, resulting in greater economic efficiency and practicality. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 This is the hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 6 of the present invention; Figure 2 This is the result of investigating the catalyst life of Example 9 of the present invention. DETAILED DESCRIPTION

[0024] The deprotection reaction formula is as follows:

[0025] Catalyst performance evaluation conditions: A catalyst with a diameter of 1.2-1.5 mm was loaded into a stainless steel fixed-bed reactor with an inner diameter of 15 mm. The heating furnace was started. After the catalyst bed temperature reached the set point, the plunger pump was activated to control the feed rate of the reactant, p-tert-butyloxyphenethyl methyl ether. The reaction liquid was vaporized in a preheater and then entered the reactor. The reaction occurred in the catalyst bed and then entered a gas-liquid separator. The liquid product was collected and the gaseous product (isobutylene) was discharged. The liquid product was quantitatively analyzed using a gas chromatograph, and the conversion and selectivity were calculated.

[0026] The calculation method of the catalyst loading of the present invention is as follows: Loading amount = nitrate mass * metal atomic weight / (nitrate molecular weight * aluminum phosphate mass) * 100% Example 1

[0027] K-modified aluminum phosphate was used as the catalyst, with a K loading of 1 wt%. Catalyst preparation method: 0.21 g potassium nitrate was dissolved in 8 g deionized water, heated to 50°C, and 8 g aluminum phosphate was added to the solution. The solution was allowed to stand for 30 minutes, dried at 110°C for 12 hours, and then calcined at 450°C in air or nitrogen atmosphere for 4 hours to prepare a solid acid catalyst. The catalyst performance evaluation results are shown in Table 1. The reaction temperature was 210°C, and the liquid space velocity was 1 h. -1 , the reaction pressure is normal pressure. Example 2

[0028] A Ca-modified aluminum phosphate catalyst was used, with a Ca loading of 1 wt%. Catalyst preparation method: 0.33 g of calcium nitrate was dissolved in 8 g of deionized water, heated to 50°C, and 8 g of aluminum phosphate was added to the solution. The solution was allowed to stand for 30 minutes, dried at 110°C for 12 hours, and then calcined at 450°C in air or nitrogen atmosphere for 4 hours to prepare a solid acid catalyst. The catalyst performance evaluation results are shown in Table 1. The reaction temperature was 210°C, and the liquid space velocity was 1 h -1 , the reaction pressure is normal pressure. Example 3

[0029] Na-modified aluminum phosphate was used as the catalyst, with a Na loading of 1 wt%. Catalyst preparation method: 0.3 g of sodium nitrate was dissolved in 8 g of deionized water, heated to 50°C, 8 g of aluminum phosphate was added to the solution, allowed to stand for 30 minutes, dried at 110°C for 12 hours, and then calcined at 450°C in air or nitrogen atmosphere for 4 hours to prepare a solid acid catalyst. The catalyst performance evaluation results are shown in Table 1. The reaction temperature was 210°C and the liquid space velocity was 1 h -1 , the reaction pressure is normal pressure. Example 4

[0030] Mg-modified aluminum phosphate was used as the catalyst, with a Mg loading of 1 wt%. Catalyst preparation method: 0.49 g of magnesium nitrate was dissolved in 8 g of deionized water, heated to 50°C, 8 g of aluminum phosphate was poured into the above solution, allowed to stand for 30 minutes, dried at 110°C for 12 hours, and then calcined at 450°C in air or nitrogen atmosphere for 4 hours to prepare a solid acid catalyst. The catalyst performance evaluation results are shown in Table 1. The reaction temperature was 210°C and the liquid space velocity was 1 h -1 , the reaction pressure is normal pressure. Example 5

[0031] Ba-modified aluminum phosphate was used as the catalyst, with a Ba loading of 1 wt%. Catalyst preparation method: 0.16 g of barium nitrate was dissolved in 8 g of deionized water, heated to 50°C, 8 g of aluminum phosphate was poured into the above solution, allowed to stand for 30 minutes, dried at 110°C for 12 hours, and then calcined at 450°C in air or nitrogen atmosphere for 4 hours to prepare a solid acid catalyst. The catalyst performance evaluation results are shown in Table 1. The reaction temperature was 210°C and the liquid space velocity was 1 h -1 , the reaction pressure is normal pressure. Example 6

[0032] Ba-modified aluminum phosphate was used as the catalyst, with a Ba loading of 5 wt%. Catalyst preparation method: 0.8 g of barium nitrate was dissolved in 8 g of deionized water, heated to 50°C, 8 g of aluminum phosphate was poured into the above solution, allowed to stand for 30 minutes, dried at 110°C for 12 hours, and then calcined at 450°C in air or nitrogen atmosphere for 4 hours to prepare a solid acid catalyst. The catalyst performance evaluation results are shown in Table 1. The reaction temperature was 210°C and the liquid space velocity was 1 h -1 The reaction pressure is atmospheric pressure. After the reaction, the mixed gas enters a gas-liquid separator to collect the liquid product, and the gas product (isobutylene) is vented. The collected liquid product is separated by vacuum distillation to obtain the deprotected product p-(2-methoxy)ethylphenol and the unreacted raw material p-tert-butoxyphenethyl methyl ether. The raw materials are recycled to the deprotection reaction. The gas phase analysis purity of the distilled product is 99.89%, and its nuclear magnetic resonance hydrogen spectrum is shown. Figure 1 . Example 7

[0033] Ba-modified aluminum phosphate was used as the catalyst, wherein the Ba loading was 1 wt%. The catalyst preparation method was the same as that in Example 5. The catalyst performance evaluation results are shown in Table 1. The reaction temperature was 250°C, the liquid space velocity was 1 h -1 , the reaction pressure is normal pressure. Example 8

[0034] Ba-modified aluminum phosphate was used as the catalyst, wherein the Ba loading was 1 wt%. The catalyst preparation method was the same as that in Example 5. The catalyst performance evaluation results are shown in Table 1. The reaction temperature was 250°C, the liquid space velocity was 2 h -1 , the reaction pressure is normal pressure. Example 9

[0035] Same as Example 6, reaction temperature 210 ° C, liquid space velocity 1h -1 The reaction pressure was normal pressure, and the reaction was carried out for 150 hours to investigate the catalyst life. The results were as follows: Figure 2 shown.

[0036] Comparative Example 1 Nb+W modified γ-alumina was used as the catalyst, where the loading of Nb and W was 5 wt% and the specific surface area of ​​γ-alumina was 150 m 2 / g, pore volume is 0.5cm 3 / g, with an average pore size of 16nm. Catalyst preparation method: dissolve 1.73g of niobium oxalate in 6g of deionized water, heat to 50°C, pour 6g of γ-alumina into the above solution, let it stand for 30 minutes, dry at 110°C for 12 hours, and calcine at 450°C in an air atmosphere for 4 hours to obtain a Nb-modified γ-alumina catalyst. Dissolve 0.61g of ammonium tungstate pentahydrate in 6g of deionized water, heat to 50°C, pour the Nb-modified γ-alumina catalyst into the above solution, let it stand for 30 minutes, dry at 110°C for 12 hours, and calcine at 450°C in an air atmosphere for 4 hours to obtain a catalyst. The catalyst performance evaluation results are shown in Table 1. The reaction temperature is 170°C, the liquid space velocity is 1h -1 , the reaction pressure is normal pressure.

[0037] Comparative Example 2 The catalyst of Comparative Example 1 was used, the reaction temperature was 210°C, the liquid space velocity was 1h -1 , the reaction pressure is normal pressure.

[0038] Table 1 Catalyst performance evaluation results of the examples

[0039] In summary, the present invention can realize the continuous production operation of the deprotection reaction of tert-butoxyphenethyl methyl ether, the selectivity of p-(2-methoxy)ethylphenol can reach more than 98%, and the catalyst has good stability. The continuous reaction is 150 hours (such as Figure 2 (As shown), the catalyst showed no deactivation. Furthermore, the catalyst can withstand higher temperatures and space velocities, making it more suitable for industrial applications. Although the single-pass conversion rate does not reach 100%, distillation can be used to separate the product from the unreacted feedstock, which can then be fed into the fixed-bed reactor.

[0040] The above embodiments can enable those skilled in the art to more fully understand the present invention, but do not limit the present invention in any way.

Claims

1. A deprotection method for tert-butoxyphenethyl methyl ether, characterized in that: include: Under the action of a solid acid catalyst, tert-butoxyphenethyl methyl ether is heated to undergo a deprotection reaction to obtain p-(2-methoxy)ethylphenol; The solid acid catalyst includes aluminum phosphate and an alkaline metal oxide modified on the aluminum phosphate. The metal elements contained in the alkaline metal oxide include one or more of K, Ca, Na, Ba or Mg.

2. The deprotection method of p-tert-butoxyphenethyl methyl ether according to claim 1, wherein The loading amount of the metal element on the aluminum phosphate is 1 to 5 wt %.

3. The deprotection method of p-tert-butoxyphenethyl methyl ether according to claim 1, wherein The solid acid catalyst is prepared by the following method: The solid acid catalyst is obtained by heating an aqueous solution containing one or more nitrates of K, Ca, Na, Ba, and Mg, adding aluminum phosphate, modifying the solution by an impregnation method, and drying and calcining the solution.

4. The deprotection method of p-tert-butoxyphenethyl methyl ether according to claim 3, wherein During the preparation of the solid acid catalyst, the heating temperature is 40-60° C. and the immersion time is 20-40 minutes.

5. The deprotection method of p-tert-butoxyphenethyl methyl ether according to claim 3, wherein During the preparation of the solid acid catalyst, the drying temperature is 100-120° C., and the drying time is 10-14 hours; the roasting temperature is 350-450° C., and the roasting time is 3-7 hours.

6. The deprotection method of p-tert-butoxyphenethyl methyl ether according to any one of claims 1 to 5, characterized in that The solid acid catalyst is filled in a fixed-bed continuous reactor, and then p-tert-butoxyphenethyl methyl ether is introduced into the fixed-bed continuous reactor to perform a deprotection reaction.

7. The deprotection method of p-tert-butoxyphenethyl methyl ether according to claim 6, wherein The reaction temperature is 210-250℃, and the liquid space velocity is 1-2h -1 .

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