A continuous process for the synthesis of p-tert-butoxychlorobenzene

Abstract

The application discloses a continuous synthesis method of p-tert-butoxychlorobenzene and belongs to the technical field of organic synthesis. The method comprises the following steps: continuously pumping a p-chlorophenol solution and an isobutene solution into a tower reactor to perform reaction, and continuously feeding the reaction liquid into an extraction tower to perform separation and purification. The application realizes the full-process continuity from reaction to post-treatment by combining the tower reactor with continuous extraction, greatly improves production efficiency, and has the advantages that the method can be efficiently reacted under mild conditions, process control is stable, side reactions are effectively inhibited, the yield of the product is high, meanwhile, the equipment is safe and reliable, the comprehensive production cost is significantly reduced, and the method is suitable for industrial large-scale application.

Description

Technical Field

[0001] This invention relates to a continuous synthesis method for the etherification protection reaction of phenolic hydroxyl groups, and more specifically to a continuous synthesis method for p-tert-butoxychlorobenzene. Background Technology

[0002] With the aging of society and the continuous improvement of living standards, cardiovascular diseases have gradually become the most important diseases affecting human health. The development and production of cardiovascular drug prodrugs and intermediates will inevitably have a broad market prospect, making it an important direction.

[0003] Metoprolol is a commonly used cardiovascular drug, belonging to the beta-blocker class. It regulates heart rate and lowers blood pressure, primarily used to treat heart-related diseases such as hypertension, angina pectoris, arrhythmia, myocardial infarction, and heart failure, as well as conditions caused by abnormal thickening of the myocardium and tearing of the aortic wall. It can also prevent further deterioration of cardiac function. It also relieves symptoms such as rapid heartbeat caused by hyperthyroidism and palpitations and shortness of breath caused by cardiac nerve dysfunction.

[0004] In the synthetic route of metoprolol, p-methoxyethylphenol is a key intermediate, which is usually derived from p-tert-butoxychlorobenzene, and its structural formula is as follows:

[0005]

[0006] Currently, the synthesis of p-tert-butoxychlorobenzene mainly uses p-chlorophenol and isobutylene as raw materials, and is obtained through a Friedel-Crafts alkylation reaction under acid catalysis.

[0007] Chinese patent CN100482629C discloses a typical batch synthesis method. This method involves reacting a mixture of p-chlorophenol and isobutylene in a stirred tank using concentrated sulfuric acid as a catalyst under water bath cooling. However, this batch process has significant limitations. Its operation includes several non-productive steps, leading to low production efficiency; simultaneously, uneven heat and mass transfer within the large three-necked flask easily causes large fluctuations in product yield and purity between batches, making it difficult to guarantee stability.

[0008] To overcome the shortcomings of batch processes, continuous synthesis methods have been developed in existing technologies. For example, Chinese patent CN119822934A discloses a method for synthesizing p-tert-butoxyhalobenzenes (including p-tert-butoxychlorobenzene) using a continuous flow microreactor. This method continuously pumps the raw materials and catalyst into a mixing unit and an addition unit for reaction, and the reaction solution is then post-processed to obtain the product. Although this method achieves continuous reaction, it still faces bottlenecks in industrial application. First, its harsh cryogenic reaction conditions (-5°C) and high borosilicate glass material not only lead to a sharp increase in energy consumption and high costs, but also pose safety hazards and difficulties in scale-up. More importantly, this method still uses traditional batch extraction for post-processing after continuous reaction, resulting in a mismatch between the front-end and back-end processes, creating a new bottleneck in production efficiency and failing to achieve truly continuous production throughout the entire process.

[0009] Publication No. CN 108640821 A discloses a highly efficient and continuous method and apparatus for synthesizing p-chlorophenyl tert-butyl ether. The method includes: continuously feeding a mixture of p-chlorophenol and toluene into a stirred three-necked flask for etherification; continuously adding an AlCl3 catalyst supported on activated clay to the flask; and simultaneously adding isobutylene for reaction. The continuously discharged reaction liquid is heated to 50–70°C and then enters a flash tank. The bottom material of the flash tank is separated from the slurry catalyst by a hydrocyclone. The reaction liquid is then subjected to alkaline washing and neutralization, water washing, and flash evaporation to obtain high-purity p-chlorophenyl tert-butyl ether. This method has advantages such as high efficiency, continuous operation, minimal environmental impact, and suitability for large-scale production. However, the conversion rate of this continuous method is not high, with a maximum conversion rate of only 72.6%.

[0010] In summary, existing technologies are either inefficient and unstable due to intermittent operation, or difficult to industrialize due to harsh continuous process conditions, insufficient conversion rates, and discontinuous post-processing. Therefore, there is an urgent need in this field to develop a new method for the synthesis of p-tert-butoxychlorobenzene that can operate stably under mild conditions, has safe and reliable equipment, and enables a fully continuous process. Summary of the Invention

[0011] The technical problem to be solved by the present invention is to provide a new method for synthesizing p-tert-butoxychlorobenzene. This method can realize continuous reaction, significantly improve production efficiency and reaction stability, while better controlling side reactions, achieving high reaction yield and significantly reducing production costs.

[0012] A continuous synthesis method for p-tert-butoxychlorobenzene includes the following steps:

[0013] (1) Prepare a p-chlorophenol solution by mixing p-chlorophenol, toluene, and an acid catalyst;

[0014] (2) Isobutylene is dissolved in toluene to obtain an isobutylene solution;

[0015] (3) The two prepared solutions are simultaneously and continuously pumped into the tower reactor. The reacted liquid flows out of the reactor and into the receiving tank.

[0016] (4) The reaction liquid in the receiving tank is continuously pumped into the lower part of the extraction tower, and the aqueous solution of alkali and water are pumped into the upper part of the extraction tower for countercurrent extraction and separation. The organic phase obtained by separation is p-tert-butoxychlorobenzene toluene solution. After concentration and recovery of toluene, the product p-tert-butoxychlorobenzene is obtained. Unreacted p-chlorophenol reacts with liquid alkali to generate phenolate dissolved in the aqueous phase.

[0017] In step (1) of the present invention, the weight ratio of p-chlorophenol and toluene is 1:0.5 to 3; more preferably 1:1 to 1.5.

[0018] In step (1) of the present invention, the catalyst is selected from at least one of sulfuric acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, and methanesulfonic acid, preferably sulfuric acid; the weight ratio of p-chlorophenol to acid catalyst is 1:0.001 to 0.01, preferably 1:0.003 to 0.007.

[0019] In step (2) of the present invention, the weight ratio of isobutylene to toluene is 1:1 to 4, preferably 1:1.5 to 2.

[0020] In step (3) of the present invention, the molar ratio of p-chlorophenol to isobutylene is 1:1 to 1.3, preferably 1:1.05 to 1.2.

[0021] In step (3) of the present invention, the reaction temperature of the heating reaction is 0 to 25°C, preferably 10 to 20°C.

[0022] In step (3) of the present invention, the length-to-diameter ratio of the tower reactor is 5 to 20, and more preferably 10 to 15.

[0023] In this invention, the type of reactor has a crucial impact on the reaction results. The tower reactor is a packed tower, and the packing type is at least one of Raschig rings, Pall rings, stepped rings, saddle rings, and corrugated packing, preferably Pall rings or saddle rings, and most preferably saddle rings with a diameter of 2.0~4.0 mm; the material is ceramic or polytetrafluoroethylene (PTFE); PTFE is preferred. Furthermore, the flow rate of the continuous reaction also has a significant impact on the reaction results. Based on the p-chlorophenol solution, a concentration of 40~60 wt% and a flow rate of 350~600 g / h result in a high reaction yield and ensure a good reaction rate.

[0024] In step (4) of the present invention, the alkali is selected from at least one of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, and potassium carbonate, preferably sodium hydroxide.

[0025] After adjusting the pH of the aqueous phase obtained in step (4) of this invention with acid, toluene is added for extraction and separation. After the organic phase is concentrated and toluene is recovered, p-chlorophenol is obtained and applied to the next step.

[0026] The acid is one or more of hydrochloric acid, sulfuric acid, and nitric acid, with hydrochloric acid being preferred.

[0027] Compared with the prior art, the continuous synthesis method of p-tert-butoxychlorobenzene provided by the present invention has the following significant advantages:

[0028] First, it achieves continuous operation throughout the entire process, significantly improving production efficiency. This invention combines a tower reactor with a continuous extraction tower, completely solving the bottleneck of "continuous reaction, intermittent post-processing" in existing technologies. Combined with raw material recovery and reuse, it significantly improves equipment utilization and overall production efficiency.

[0029] Secondly, the reaction conditions are mild, the equipment is safe, and it is easy to scale up industrially. This invention can achieve efficient reaction at a mild temperature of 0-25℃, without the need for cryogenic equipment, significantly reducing energy consumption. Furthermore, the ceramic or PTFE tower reactor used is safer and easier for large-scale industrial application compared to glass microchannel equipment.

[0030] Third, the process control is stable, resulting in high product yield and selectivity. Through optimized tower reactor structure and precise process parameter control, the reaction process is stable, effectively suppressing the occurrence of side reactions and ensuring high selectivity and high yield of the product, with uniform and controllable product quality.

[0031] Fourth, overall costs are significantly reduced, and the process is environmentally friendly. Mild reaction conditions and an efficient raw material and solvent recovery system together lower energy consumption, raw material costs, and operating costs. The entire process reduces emissions of waste gas, wastewater, and solid waste, meeting the requirements of green chemistry production. Detailed Implementation

[0032] The present invention will be further described in detail below through examples. The general steps of the present invention are as follows: a. Add p-chlorophenol, toluene, and catalyst to mixing tank 1 in proportion to prepare p-chlorophenol solution; b. Add toluene and isobutylene to mixing tank 2 in proportion to prepare isobutylene solution; c. Pump the two prepared solutions into a tower reactor in proportion, and the reacted liquid flows out of the reactor and enters a receiving tank; d. Pump the reaction liquid, alkali, and water in the receiving tank into an extraction tower for extraction and separation; e. After concentrating the organic phase and recovering toluene, the product p-tert-butoxychlorobenzene is obtained; d. After adjusting the pH of the aqueous phase with acid, add toluene for extraction and separation, and after concentrating the organic phase and recovering toluene, p-chlorophenol is obtained, which is then applied to step a.

[0033] Example 1

[0034] In a 3000mL three-necked flask (a), add 1000g of p-chlorophenol, 1000g of toluene, and 5g of sulfuric acid, and stir until homogeneous to obtain a p-chlorophenol solution for later use. In a three-necked flask (b), add 1000g of toluene and 500g of isobutylene, and stir until homogeneous to obtain an isobutylene solution for later use. The tower reactor has an aspect ratio of 12 and is packed with polytetrafluoroethylene saddle ring packing (Φ2.5mm). p-Chlorophenol solution and isobutylene solution were continuously pumped into the bottom of a tower reactor at flow rates of 401 g / h and 300 g / h, respectively, for mixing and reaction. The reaction temperature was controlled at 10–15 °C, and the residence time was approximately 2.5 hours. The reaction solution overflowed from the top of the tower into a receiving tank and was continuously pumped into the lower part of the extraction tower at a flow rate of 701 g / h. 30% sodium hydroxide solution and water were continuously pumped into the upper part of the extraction tower at flow rates of 50 g / h and 100 g / h, respectively, for countercurrent extraction. The organic phase overflowing from the top of the tower was a p-tert-butoxychlorobenzene-toluene solution, which was collected in a three-necked flask. Toluene was recovered by concentration under reduced pressure, yielding 1135 g of p-tert-butoxychlorobenzene, with a yield of 86.5% (based on p-chlorophenol). The GC chromatographic purity was 99.56%, with a maximum single impurity of 0.11%. The aqueous phase was collected in a three-necked flask, and the pH was adjusted to 2 with hydrochloric acid. 500 g of toluene was added for extraction and separation. The organic phase was concentrated to dryness to obtain 134 g of recovered p-chlorophenol.

[0035] Example 2

[0036] 1000g of p-chlorophenol, 1200g of toluene, and 6g of sulfuric acid were added to a 3000mL three-necked flask (a), and stirred until homogeneous to obtain a p-chlorophenol solution for later use. 800g of toluene and 500g of isobutylene were added to a three-necked flask (b), and stirred until homogeneous to obtain an isobutylene solution for later use. The tower reactor has an aspect ratio of 12 and is packed with polytetrafluoroethylene saddle ring packing (Φ2.5mm). p-Chlorophenol solution and isobutylene solution were continuously pumped into the bottom of a tower reactor at flow rates of 551.5 g / h and 325 g / h, respectively, for mixing and reaction. The reaction temperature was controlled at 10–15 °C, and the residence time was approximately 2.2 hours. The reaction liquid overflowed from the top of the tower into a receiving tank and was continuously pumped into the lower part of the extraction tower at a flow rate of 876.5 g / h. Liquid alkali and water were continuously pumped into the upper part of the extraction tower at a flow rate of 60 g / h and 120 g / h, respectively, for countercurrent extraction. The organic phase overflowing from the top of the tower was a p-tert-butoxychlorobenzene-toluene solution, which was collected in a three-necked flask. Toluene was recovered by vacuum concentration, yielding 1153 g of p-tert-butoxychlorobenzene, with a yield of 87.9% (based on p-chlorophenol). The GC chromatographic purity was 99.63%, with a maximum single impurity of 0.09%. The aqueous phase was collected in a three-necked flask, and the pH was adjusted to 2 with hydrochloric acid. 500 g of toluene was added for extraction and separation. The organic phase was concentrated to dryness to obtain 121 g of recovered p-chlorophenol.

[0037] Example 3

[0038] 1000g of p-chlorophenol, 1000g of toluene, and 5g of sulfuric acid were added to a 3000mL three-necked flask (a), and stirred until homogeneous to obtain a p-chlorophenol solution for later use. 1000g of toluene and 500g of isobutylene were added to a three-necked flask (b), and stirred until homogeneous to obtain an isobutylene solution for later use. The tubular reactor is 20m long and has an inner diameter of 2mm. p-Chlorophenol solution and isobutylene solution were continuously pumped into the bottom of a tubular reactor at flow rates of 35 g / h and 26 g / h, respectively, for mixing and reaction. The reaction temperature was controlled at 10–15 °C, and the residence time was approximately 2.1 hours. The reaction liquid flowed to a receiving tank and was continuously pumped into the lower part of an extraction column at a flow rate of 61 g / h. 30% sodium hydroxide solution and water were continuously pumped into the upper part of the extraction column at flow rates of 4.5 g / h and 9 g / h, respectively, for countercurrent extraction. The organic phase overflowing from the top of the column was a p-tert-butoxychlorobenzene-toluene solution, which was collected in a three-necked flask. Toluene was recovered by concentration under reduced pressure, yielding 936 g of p-tert-butoxychlorobenzene, with a yield of 71.3% (based on p-chlorophenol). The GC chromatographic purity was 99.27%, with a maximum single impurity of 0.27%. The aqueous phase was collected in a three-necked flask, and the pH was adjusted to 2 with hydrochloric acid. 500 g of toluene was added for extraction and separation. The organic phase was concentrated to dryness to obtain 286 g of recovered p-chlorophenol.

[0039] The results of Example 3 show that the reaction can occur when a tubular reactor is used, but the product yield is significantly reduced, and the flow rate of the device cannot be too fast.

[0040] Example 4

[0041] 1000g of p-chlorophenol, 1000g of toluene, and 5g of sulfuric acid were added to a 3000mL three-necked flask (a), and stirred until homogeneous to obtain a p-chlorophenol solution for later use. 1000g of toluene and 500g of isobutylene were added to a three-necked flask (b), and stirred until homogeneous to obtain an isobutylene solution for later use. The column reactor has a length-to-diameter ratio of 12, and the empty column is unpacked. p-Chlorophenol solution and isobutylene solution were continuously pumped into the bottom of a tower reactor at flow rates of 401 g / h and 300 g / h, respectively, for mixing and reaction. The reaction temperature was controlled at 10–15 °C, and the residence time was approximately 3 hours. The reaction solution overflowed from the top of the tower into a receiving tank and was then continuously pumped into the lower part of an extraction tower at a flow rate of 701 g / h. 30% sodium hydroxide solution and water were continuously pumped into the upper part of the extraction tower at flow rates of 50 g / h and 100 g / h, respectively, for countercurrent extraction. The organic phase overflowing from the top of the tower was a p-tert-butoxychlorobenzene-toluene solution, which was collected in a three-necked flask. Toluene was recovered by concentration under reduced pressure, yielding 743.7 g of p-tert-butoxychlorobenzene, with a yield of 56.7% (based on p-chlorophenol). The GC chromatographic purity was 99.16%, with a maximum single impurity of 0.31%. The aqueous phase was collected in a three-necked flask, and the pH was adjusted to 2 with hydrochloric acid. 500 g of toluene was added for extraction and separation. The organic phase was concentrated to dryness to obtain 433 g of recovered p-chlorophenol.

[0042] The results of Example 4 show that when a tower reactor is used for the reaction, but no packing is added, the reaction can still occur, but the yield of the product is significantly reduced.

[0043] Example 5

[0044] 1000g of p-chlorophenol, 1000g of toluene, and 5g of sulfuric acid were added to a 3000mL three-necked flask (a), and stirred until homogeneous to obtain a p-chlorophenol solution for later use. 1000g of toluene and 500g of isobutylene were added to a three-necked flask (b), and stirred until homogeneous to obtain an isobutylene solution for later use. The tower reactor has a length-to-diameter ratio of 12 and is packed with polytetrafluoroethylene saddle ring packing. p-Chlorophenol solution and isobutylene solution were continuously pumped into the bottom of a tower reactor at flow rates of 802 g / h and 600 g / h, respectively, for mixing and reaction. The reaction temperature was controlled at 10–15 °C, and the residence time was approximately 1.25 hours. The reaction solution overflowed from the top of the tower into a receiving tank and was continuously pumped into the lower part of the extraction tower at a flow rate of 1402 g / h. 30% sodium hydroxide solution and water were continuously pumped into the upper part of the extraction tower at flow rates of 100 g / h and 200 g / h, respectively, for countercurrent extraction. The organic phase overflowing from the top of the tower was a p-tert-butoxychlorobenzene-toluene solution, which was collected in a three-necked flask. Toluene was recovered by vacuum concentration, yielding 901.7 g of p-tert-butoxychlorobenzene, with a yield of 68.7% (based on p-chlorophenol). The GC chromatographic purity was 99.50%, with a maximum single impurity of 0.15%. The aqueous phase was collected in a three-necked flask, and the pH was adjusted to 2 with hydrochloric acid. 500 g of toluene was added for extraction and separation. The organic phase was concentrated to dryness to obtain 312 g of recovered p-chlorophenol.

[0045] The results of Example 5 show that if the flow rate is too high, it will also lead to a decrease in yield.

[0046] Comparative Example 1

[0047] 1000g of p-chlorophenol, 1200g of toluene, and 6g of sulfuric acid were added to a 3000mL three-necked flask. The mixture was stirred and cooled to 10-15℃. 500g of isobutylene was added, and the reaction was maintained at 10-15℃ for 2 hours. 400g of water and 300g of lye were added, and the mixture was extracted and separated. The organic phase was concentrated under reduced pressure to recover toluene, yielding 918g of p-tert-butoxychlorobenzene, with a yield of 70.0% (based on p-chlorophenol). The GC chromatographic purity was 98.93%, with a maximum single impurity of 0.37%. The aqueous phase was adjusted to pH 2 with hydrochloric acid, and 500g of toluene was added for extraction and separation. The organic phase was concentrated to dryness to recover 300g of p-chlorophenol.

[0048] The above description is merely a basic explanation of the concept of this invention, and any equivalent modifications made based on the technical solution of this invention shall fall within the protection scope of this invention.

Claims

1. A continuous synthesis method for p-tert-butoxychlorobenzene, characterized in that, Includes the following steps: (1) Prepare a p-chlorophenol solution by mixing p-chlorophenol, toluene, and an acid catalyst; (2) Dissolve isobutylene in toluene to obtain an isobutylene solution; (3) The two prepared solutions are simultaneously and continuously pumped into the bottom of the tower reactor for mixing and reaction. After the reaction is completed, the liquid overflows from the top of the tower to the receiving tank. (4) The reaction liquid in the receiving tank is continuously pumped into the lower part of the extraction tower, and the aqueous solution of alkali and water are pumped into the upper part of the extraction tower for countercurrent extraction and separation. The organic phase obtained by separation is p-tert-butoxychlorobenzene toluene solution. After concentration and recovery of toluene, the product p-tert-butoxychlorobenzene is obtained. Unreacted p-chlorophenol reacts with the aqueous solution of alkali to form phenolate dissolved in the aqueous phase. In step (3), the length-to-diameter ratio of the tower reactor is 10 to 15; The tower reactor is a packed tower, and the packing type is saddle rings with a diameter of Φ2.0~4.0mm, made of ceramic or polytetrafluoroethylene. Based on the p-chlorophenol solution, the concentration of the p-chlorophenol solution is 40~60 wt%, and the flow rate is 350~600 g / h; In step (3), the molar ratio of p-chlorophenol to isobutylene is 1:1 to 1.3; In step (3), the reaction temperature range is 10 to 20°C.

2. The continuous synthesis method for p-tert-butoxychlorobenzene according to claim 1, characterized in that, In step (1), the weight ratio of p-chlorophenol and toluene is 1:0.5 to 3.

3. The continuous synthesis method for p-tert-butoxychlorobenzene according to claim 1, characterized in that, In step (1), the acid catalyst is one or more of sulfuric acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, and methanesulfonic acid; The weight ratio of p-chlorophenol to acid catalyst is 1:0.001 to 0.

01.

4. The continuous synthesis method for p-tert-butoxychlorobenzene according to claim 1, characterized in that, In step (2), the weight ratio of isobutylene to toluene is 1:1 to 4.

5. The continuous synthesis method for p-tert-butoxychlorobenzene according to claim 1, characterized in that, In step (4), the alkali is one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, and potassium carbonate.

6. The continuous synthesis method for p-tert-butoxychlorobenzene according to claim 1, characterized in that, After adjusting the pH of the aqueous phase obtained in step (4) with acid, toluene was added for extraction and separation. The organic phase was concentrated and toluene was recovered to obtain p-chlorophenol, which was then applied to step (1). The acid mentioned is one or more of hydrochloric acid, sulfuric acid, and nitric acid.

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