Method for continuously producing benzethonium chloride

Abstract

The invention belongs to the technical field of benzethonium chloride production methods, and particularly relates to a method for continuously producing benzethonium chloride, which comprises the following steps: S1, dissolving p-tert-octylphenol in dichlorodiethyl ether at room temperature to prepare a p-tert-octylphenol-dichlorodiethyl ether mixed solution; pumping the p-tert-octylphenol-dichlorodiethyl ether mixed solution and a potassium hydroxide solution with the concentration of 10-80% into a reaction kettle by a continuous flow method for etherification reaction, adding water for extraction and layering, separating out a lower water layer, and washing an organic phase at the lower layer twice; and S2, after washing, desolventizing under reduced pressure to recover dichlorodiethyl ether, so as to obtain p-tert-octyl phenoxy ethyoxyl ethyl chloride. According to the invention, the yield and purity of the product and the utilization rate of the raw materials can be improved at a relatively low temperature within a relatively short reaction time, and the production efficiency is ensured.

Description

Technical Field

[0001] The invention belongs to the technical field of benzethonium chloride production methods, and specifically relates to a method for continuously producing benzethonium chloride. Background Art

[0002] Benzethonium chloride is a quaternary ammonium salt cationic surfactant that dissolves readily in water to form a foamy, soapy solution. It exhibits broad-spectrum antibacterial, disinfectant, and cleansing properties. As a new-generation detergent, disinfectant, and preservative, it has applications in the pharmaceutical field, often for skin and mucous membrane disinfection, medical device disinfection, and environmental cleaning. Its mechanism of action is to disrupt microbial cell membranes, inhibiting the activity of bacteria, fungi, and some viruses.

[0003] At the same time, benzethonium chloride can also be used in the synthesis of enoxaparin sodium. Enoxaparin sodium is a new generation of heparin anticoagulant drugs prepared by the alkaline β-elimination method using porcine intestinal mucosal heparin as the starting material. It is a super blockbuster drug among anticoagulant drugs and one of the best drugs for the treatment and prevention of cerebral thrombosis. It has the characteristics of strong antithrombotic effect and low bleeding risk. Clinical trials have shown that enoxaparin sodium can achieve significant effects of anticoagulation and anti-thrombosis.

[0004] After searching, a Chinese patent with publication number CN114805096A (publication date 2022.07.29) discloses a production and preparation process of benzethonium chloride, comprising the following steps: a. Using 4-tert-octylphenol and chloroethanol as raw materials to prepare 2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)ethan-1-ol; b. Then using 2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)ethan-1-ol and (β-chloroethyl)dimethylamine as raw materials to prepare N,N-dimethyl-2-(2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)ethoxy)ethan-1-amine; c. Then using N,N-dimethyl-2-(2-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)ethoxy)ethan-1-amine and benzyl chloride as raw materials to prepare benzethonium chloride. This invention uses 4-tert-octylphenol, chloroethanol, and (β-chloroethyl)dimethylamine as raw materials and conducts a three-step synthesis, all under normal pressure. However, due to the long reaction times of more than 4 hours in each of the three steps, and the need for gradient temperature control, a continuous flow process cannot be used, severely impacting production efficiency.

[0005] Chinese patent publication number CN118084685A (published on May 28, 2024) discloses a continuous pipeline preparation method for benzethonium chloride, comprising the following steps: S1: preparing compound 3; S2: preparing crude compound 1; and S3: purifying compound 1. This invention employs continuous pulsed delivery of 4-tert-octylphenoxyethoxyethyl chloride and a dimethylamine aqueous solution to a tubular reactor at a process temperature. The feed rate, reaction pressure, and reaction time are controlled, and the product is continuously discharged under reduced pressure. The product is then fed to a crude product receiving tank, allowed to stand to separate the water layer, and the organic layer is pumped into a distillation apparatus for collection by high vacuum distillation to obtain compound 3. However, in step S2 of this invention, 4-tert-octylphenoxyethoxyethyl chloride is used to prepare the intermediate compound 3 (4-tert-octylphenoxyethoxyethyldimethylamine). However, the yield of compound 3 (4-tert-octylphenoxyethoxyethyldimethylamine) is less than 86%, which is a low yield and seriously affects the efficiency of subsequent benzethonium chloride synthesis. ‌‌ Summary of the Invention

[0006] The object of the present invention is to provide a method for continuously producing benzethonium chloride, to solve the problems raised in the above-mentioned background technology.

[0007] To achieve the above object, the present invention provides the following technical solution, a method for continuously producing benzethonium chloride, comprising the following steps: S1, at room temperature, 4-tert-octylphenol was dissolved in dichlorodiethyl ether to prepare a 4-tert-octylphenol-dichlorodiethyl ether mixed solution, and then the 4-tert-octylphenol-dichlorodiethyl ether mixed solution and a potassium hydroxide solution with a concentration of 10-80% were pumped into a reactor in a continuous flow method to carry out etherification reaction, and after water extraction and layering, the lower aqueous layer was separated, and the organic phase of the lower layer was washed twice; S2, after washing, desolventizing and recovering dichlorodiethyl ether to obtain 4-tert-octylphenoxyethoxyethyl chloride; S3, the 4-tert-octylphenoxyethoxyethyl chloride, dimethylamine aqueous solution and sodium hydroxide prepared in S2 are subjected to a substitution reaction in a high-pressure reactor to obtain a feed solution containing N,N-dimethylethoxy-4-tert-octylphenethyl ether; S4, cooling the feed solution obtained in S3 to below 35° C., standing to separate layers, taking the upper layer, washing it twice with a 5-40% sodium chloride aqueous solution at 40-50° C. to obtain an upper organic phase, and then distilling the upper organic phase under reduced pressure to remove water, thereby obtaining N,N-dimethylethoxy-p-tert-octylphenyl ether; S5. Stirring the N,N-dimethylethoxy-p-tert-octylphenyl ether and ethyl acetate prepared in S4 at room temperature until dissolved to obtain a N,N-dimethylethoxy-p-tert-octylphenyl ether-ethyl acetate mixture, and reacting the N,N-dimethylethoxy-p-tert-octylphenyl ether-ethyl acetate mixture with benzyl chloride in a continuous flow to obtain a crude benzethonium chloride product; S6, the benzethonium chloride crude product obtained in S5 is refined, ethyl acetate and anhydrous ethanol are heated to dissolve the benzethonium chloride crude product and diatomaceous earth is added to stir, and hot filtration is carried out, and the filtrate is heated to be a colorless transparent liquid and then heating is stopped, slowly cooled, filtered and fully washed with ethyl acetate, and oven dry to obtain the benzethonium chloride finished product.

[0008] As a preferred embodiment of the above technical solution, in S1, the p-tert-octylphenol-dichlorodiethyl ether mixed solution and the potassium hydroxide solution are pumped into the reactor in a continuous flow method for etherification reaction, the reaction temperature is 60-120°C, the reaction time is 2.5 hours, and the flow rate ratio of the p-tert-octylphenol-dichlorodiethyl ether mixed solution to the potassium hydroxide solution is 1:(0.15-1.5).

[0009] As a preferred embodiment of the above technical solution, the mass ratio of p-tert-octylphenol, dichlorodiethyl ether and potassium hydroxide solution in S1 is 1: (1.0-3.5): (0.1-1.0).

[0010] As a preferred embodiment of the above technical solution, the reduced pressure desolventizing and recovering dichlorodiethyl ether in S2 adopts a vacuum degree of 15 mm Hg, a material temperature ≤ 160°C, and a top temperature ≤ 150°C.

[0011] As a preferred embodiment of the above technical solution, in S3, 4-tert-octylphenoxyethoxyethyl chloride, dimethylamine aqueous solution and sodium hydroxide are subjected to substitution reaction in a high-pressure reactor at a reaction temperature of 110-120° C. and a pressure of 0.8-1.2 MPa for 6-12 hours.

[0012] As a preferred embodiment of the above technical solution, the upper organic phase in S4 is subjected to reduced pressure distillation to remove water at -0.095 MPa, material temperature ≤ 120°C, and top temperature ≤ 100°C to obtain N,N-dimethylethoxy-4-tert-octylphenyl ether.

[0013] As a preferred embodiment of the above technical solution, the mass ratio of 4-tert-octylphenoxyethoxyethyl chloride, dimethylamine aqueous solution, sodium hydroxide and sodium chloride in S3 and S4 is 1: (0.5-2.0): (0.05-1.0): (0.1-2.0).

[0014] As a preferred embodiment of the above technical solution, the N,N-dimethylethoxy-p-tert-octylphenyl ether-ethyl acetate mixture in S5 is reacted with benzyl chloride by continuous flow to obtain crude benzethonium chloride, the reaction temperature is 30-75°C, the reaction time is 12-18 hours, and the flow rate ratio of the N,N-dimethylethoxy-p-tert-octylphenyl ether-ethyl acetate mixture to benzyl chloride is 1:(0.03-0.2).

[0015] As a preferred embodiment of the above technical solution, the mass ratio of N,N-dimethylethoxy-4-tert-octylphenyl ether, ethyl acetate and benzyl chloride in S5 is 1:(2.0-8.0):(0.1-1.0).

[0016] As a preferred embodiment of the above technical solution, the mass ratio of the crude benzethonium chloride, ethyl acetate, anhydrous ethanol and diatomaceous earth in S6 is 1: (2-8): (0.1-1): (0.01-1).

[0017] Compared with the prior art, the present invention has the following beneficial effects: 1. The method for preparing 4-tert-octylphenoxyethoxyethyl chloride by a continuous flow method in S1 of the present invention can shorten the reaction time at a relatively mild reaction temperature, while achieving maximum utilization of the raw material 4-tert-octylphenol, thereby improving the yield and purity of the product 4-tert-octylphenoxyethoxyethyl chloride.

[0018] 2. In the present invention, S3 also uses a continuous flow method to pump the raw materials into the reactor for salt formation reaction. The reaction temperature is mild, the reaction efficiency is high, the process is safe and environmentally friendly, and the yield of the target product is improved.

[0019] 3. The present invention can improve the yield and purity of the product and the utilization rate of the raw materials at a lower temperature and in a shorter reaction time, thereby ensuring production efficiency. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 It is the chemical equation diagram of the synthesis reaction of the present invention. DETAILED DESCRIPTION

[0021] The technical solutions in the embodiments of the present invention will be described clearly and completely below with reference to the accompanying drawings in the embodiments of the present invention.

[0022] like Figure 1 As shown, a method for continuously producing benzethonium chloride comprises the following steps: S1, 4-tert-octylphenol was dissolved in dichlorodiethyl ether to prepare a 4-tert-octylphenol-dichlorodiethyl ether mixed solution, and then the 4-tert-octylphenol-dichlorodiethyl ether mixed solution and potassium hydroxide solution were pumped into a reactor in a continuous flow method to carry out etherification reaction, and after water extraction and layering, the lower aqueous layer was separated, and the organic phase of the lower layer was washed twice; S2, after washing, desolventizing and recovering dichlorodiethyl ether to obtain 4-tert-octylphenoxyethoxyethyl chloride; S3, subjecting the 4-tert-octylphenoxyethoxyethyl chloride, dimethylamine aqueous solution and sodium hydroxide prepared in S2 to a substitution reaction in a high-pressure reactor to obtain a feed solution containing N,N-dimethylethoxy-4-tert-octylphenyl ether; S4, cooling the liquid obtained in S3 to below 35°C, standing to separate layers, taking the upper layer, washing it twice with a sodium chloride aqueous solution at 40-50°C to obtain an upper organic phase, and then distilling the upper organic phase under reduced pressure to remove water, thereby obtaining N,N-dimethylethoxy-4-tert-octylphenyl ether; S5. Stir the N,N-dimethylethoxy-p-tert-octylphenyl ether and ethyl acetate prepared in S4 at room temperature until dissolved to obtain a N,N-dimethylethoxy-p-tert-octylphenyl ether-ethyl acetate mixture, and react the N,N-dimethylethoxy-p-tert-octylphenyl ether-ethyl acetate mixture with benzyl chloride in a continuous flow to obtain a crude benzethonium chloride product; S6. Refining the crude benzethonium chloride obtained in S5.

[0023] As a preferred embodiment of the above technical solution, in S1, p-tert-octylphenol and dichlorodiethyl ether are stirred in a container at room temperature until dissolved.

[0024] As a preferred embodiment of the above technical solution, the concentration of the potassium hydroxide solution in S1 is 10-80%.

[0025] In a specific implementation, further, the concentration of potassium hydroxide is 50%.

[0026] As a preferred embodiment of the above technical solution, in S1, the 4-tert-octylphenol-dichlorodiethyl ether mixed solution and the potassium hydroxide solution are pumped into the reactor in a continuous flow method for etherification reaction, the reaction temperature is 60-120°C, the reaction time is 2.5 hours, and the flow rate ratio of the 4-tert-octylphenol-dichlorodiethyl ether mixed solution to the potassium hydroxide solution is 1:(0.15-1.5).

[0027] In a specific implementation, the reaction temperature is further 80° C., the reaction time is 2.5 hours, and the flow rate ratio of the 4-tert-octylphenol-dichlorodiethyl ether mixed solution to the potassium hydroxide solution is 1:0.23.

[0028] As a preferred embodiment of the above technical solution, the mass ratio of p-tert-octylphenol, dichlorodiethyl ether and potassium hydroxide solution in S1 is 1: (1.0-3.5): (0.1-1.0).

[0029] In a specific implementation, the mass ratio of 4-tert-octylphenol, dichlorodiethyl ether and potassium hydroxide is 1:2.79:0.44.

[0030] As a preferred embodiment of the above technical solution, the reduced pressure desolventizing and recovering dichlorodiethyl ether in S2 adopts a vacuum degree of 15 mm Hg, a material temperature ≤ 160°C, and a top temperature ≤ 150°C.

[0031] As a preferred embodiment of the above technical solution, in S3, 4-tert-octylphenoxyethoxyethyl chloride, dimethylamine aqueous solution and sodium hydroxide are subjected to substitution reaction in a high-pressure reactor at a reaction temperature of 110-120° C. and a pressure of 0.8-1.2 MPa for 6-12 hours.

[0032] As a preferred embodiment of the above technical solution, the upper organic phase in S4 is subjected to reduced pressure distillation to remove water at -0.095 MPa, material temperature ≤120°C, and top temperature ≤100°C to obtain N,N-dimethylethoxy-4-tert-octylphenyl ether.

[0033] As a preferred embodiment of the above technical solution, the concentration of the sodium chloride aqueous solution in S4 is 5-40%.

[0034] In a specific implementation, further, the concentration of the sodium chloride aqueous solution is 20%.

[0035] As a preferred embodiment of the above technical solution, the mass ratio of 4-tert-octylphenoxyethoxyethyl chloride, dimethylamine aqueous solution, sodium hydroxide and sodium chloride in S3 and S4 is 1: (0.5-2.0): (0.05-1.0): (0.1-2.0).

[0036] In a specific implementation, further, the mass ratio of 4-tert-octylphenoxyethoxyethyl chloride, dimethylamine aqueous solution, sodium hydroxide and sodium chloride is 1:0.9:0.15:0.17.

[0037] As a preferred embodiment of the above technical solution, in S5, the N,N-dimethylethoxy-4-tert-octylphenyl ether-ethyl acetate mixture and benzyl chloride are subjected to a continuous flow salt formation reaction to obtain a crude benzethonium chloride product, the reaction temperature is 30-75°C, the reaction time is 12-18 hours, and the flow rate ratio of the N,N-dimethylethoxy-4-tert-octylphenyl ether-ethyl acetate mixture to the benzyl chloride is 1:(0.03-0.2).

[0038] In a specific implementation, further, a salt-forming reaction is carried out between a N,N-dimethylethoxy-p-tert-octylphenyl ether-ethyl acetate mixture and benzyl chloride by continuous flow to obtain a crude benzethonium chloride product. The reaction temperature is 45-50°C, the reaction time is 16 hours, and the flow rate ratio of the N,N-dimethylethoxy-p-tert-octylphenyl ether-ethyl acetate mixture to the benzyl chloride is 1:0.08.

[0039] As a preferred embodiment of the above technical solution, the mass ratio of N,N-dimethylethoxy-4-tert-octylphenyl ether, ethyl acetate and benzyl chloride in S5 is 1:(2.0-8.0):(0.1-1.0).

[0040] In a specific implementation, the mass ratio of N,N-dimethylethoxy-4-tert-octylphenyl ether, ethyl acetate and benzyl chloride is 1:4:0.4.

[0041] As a preferred embodiment of the above technical solution, in S6, ethyl acetate and anhydrous ethanol are heated to dissolve the crude benzethonium chloride and diatomaceous earth is added and stirred, and hot filtration is performed. After the filtrate is heated to a colorless transparent liquid, heating is stopped, the temperature is slowly lowered, the product is filtered and washed thoroughly with ethyl acetate, and the finished benzethonium chloride is obtained by drying.

[0042] In a specific implementation, ethyl acetate and anhydrous ethanol are further heated to 65° C. to dissolve the crude benzethonium chloride and diatomaceous earth is added, stirred for 1 hour, and hot filtered. After the filtrate is heated to a colorless transparent liquid, heating is stopped and the temperature is slowly lowered to 10° C. Filter and fully wash with ethyl acetate, and dry to obtain the finished benzethonium chloride.

[0043] Furthermore, the mass ratio of crude benzethonium chloride, ethyl acetate, anhydrous ethanol and diatomaceous earth is 1: (2-8): (0.1-1): (0.01-1).

[0044] In a specific implementation, further, the mass ratio of crude benzethonium chloride, ethyl acetate, anhydrous ethanol and diatomaceous earth is 1:5:0.25:0.05.

[0045] Example 1 Example 1: tert-octylphenoxyethoxyethyl chloride was prepared by the continuous flow process provided by S1 and S2 of the present invention.

[0046] 824 g of p-tert-octylphenol was added to a 3 L four-necked flask containing 2300 g of dichlorodiethyl ether, and stirred at room temperature until dissolved. The mixed liquid was set aside.

[0047] Use metering pumps to pump the prepared mixed solution and 730 g of 50% potassium hydroxide solution into the reaction flask respectively. The temperature of the reaction flask is maintained at 80°C, the flow rate ratio of the mixed solution to the 50% potassium hydroxide solution is 1:0.23, and the reaction is carried out for 2.5 hours. The content of tert-octylphenol in the sample is controlled at 0.947%.

[0048] The temperature was lowered to 10°C, 500.0 g of water was added to the flask, and after stirring for 30 min, the mixture was allowed to stand for stratification. The lower aqueous layer was separated, and 2×800 g of water was added to the reaction flask. The organic phase was washed twice (the organic phase was in the lower layer).

[0049] After washing, dichlorodiethyl ether was recovered by desolventizing under the conditions of -0.095 MPa, material temperature ≤160°C, and top temperature ≤150°C. After recovery, 1203.0 g of dichlorodiethyl ether was obtained, and 1232.0 g of crude 4-tert-octylphenoxyethoxyethyl chloride was obtained with a purity of 91.772% and a yield of 98.6%.

[0050] Comparative Example 1 Comparative Example 1 is compared with Example 1, except that the continuous flow process is not used to prepare 4-tert-octylphenoxyethoxyethyl chloride.

[0051] Add 824 g of 4-tert-octylphenol and 2300 g of dichlorodiethyl ether to a 5L four-necked flask, stir and heat to 80°C, add 730.0 g of 50.0% potassium hydroxide aqueous solution (prepared by 365 g of potassium hydroxide and 365 g of water) to the four-necked flask, control the addition temperature to 80-95°C, and add the solution dropwise over 1 hour.

[0052] After the addition is complete, maintain the temperature for 0.5 h, then raise the temperature to reflux (105-110°C), maintain for 2 h, take samples for central control, and control the concentration of tert-octylphenol to <1.0%.

[0053] After passing the test, cool to 10-20°C, add 500.0g of water to the flask, stir for 30min, let it stand to separate the layers, separate the lower aqueous layer, then add 2×800g of water to the reaction flask, and wash the organic phase twice (the organic phase is in the lower layer).

[0054] After washing, dichlorodiethyl ether was recovered by desolventizing under the conditions of -0.095 MPa, material temperature ≤160°C, and top temperature ≤150°C. 1267.0 g of dichlorodiethyl ether was recovered, and 1163.30 g of crude 4-tert-octylphenoxyethoxyethyl chloride was obtained with a purity of 85.353% and a yield of 93.1%.

[0055] The results of Example 1 and Comparative Example 1 are compared in Table 1.

[0056] Table 1

[0057] As can be seen from Table 1, the continuous flow process provided by S1 and S2 of the present invention is used to prepare 4-tert-octylphenoxyethoxyethyl chloride. The continuous flow method can improve the yield of 4-tert-octylphenoxyethoxyethyl chloride, and the prepared 4-tert-octylphenoxyethoxyethyl chloride has higher purity.

[0058] Comparative Example 2 Comparative Example 2 is compared with Example 1, except that the amount of dichlorodiethyl ether used is greater.

[0059] 824 g of p-tert-octylphenol was added to a 5 L four-necked flask containing 3296 g of dichlorodiethyl ether, and stirred at room temperature until dissolved. The mixed liquid was set aside.

[0060] The prepared mixed solution and 730 g of 50% potassium hydroxide solution were pumped into the reactor respectively using a metering pump. The reactor was maintained at a temperature of 80°C. The flow rate ratio of the mixed solution to the 50% potassium hydroxide solution was 1:0.18. The reaction was continued for 2.5 hours. The content of tert-octylphenol in the sample was controlled at 0.824%.

[0061] The temperature was lowered to 10°C, 500.0 g of water was added to the flask, and after stirring for 30 min, the mixture was allowed to stand for stratification. The lower aqueous layer was separated, and 2×800 g of water was added to the reaction flask. The organic phase was washed twice (the organic phase was in the lower layer).

[0062] After washing, dichlorodiethyl ether was recovered by desolventizing at -0.095 MPa, material temperature ≤160°C, and top temperature ≤150°C. 2127.6 g of dichlorodiethyl ether was recovered to obtain 1234.4 g of crude 4-tert-octylphenoxyethoxyethyl chloride with a purity of 91.923% and a yield of 98.8%.

[0063] The results of Example 1 and Comparative Example 2 are compared in Table 2.

[0064] Table 2

[0065] As can be seen from Table 2, the continuous flow process provided by S1 and S2 of the present invention is used to prepare 4-tert-octylphenoxyethoxyethyl chloride. It can greatly reduce the amount of dichlorodiethyl ether without affecting the purity and yield of 4-tert-octylphenoxyethoxyethyl chloride, effectively reducing the raw material cost and the subsequent vacuum desolventizing and recovery cost. Since it takes longer to pump dichlorodiethyl ether into the reactor when the amount is large, the production efficiency is also greatly improved.

[0066] Example 2 Example 2 The continuous flow process provided in S5 of the present invention is used to prepare crude benzethonium chloride.

[0067] Add 30.0 g of N,N-dimethylethoxy-4-tert-octylphenyl ether into a 250 ml four-necked flask containing 120.0 g of ethyl acetate and stir at room temperature until dissolved.

[0068] The mixed solution and 12.1 g of benzyl chloride were pumped into the reaction flask using a metering pump. The reaction was maintained at 45°C for 16 hours. After the reaction was qualified, the temperature was lowered to 10°C and filtered. The filter cake was rinsed twice with 50.0 g of ethyl acetate. The wet product was dried at 105°C for 2 hours. The dry weight was 38.9 g, the purity was 95.331%, and the yield was 85.4%.

[0069] Comparative Example 3 Comparative Example 3 is compared with Example 2, except that the crude benzethonium chloride product is not prepared by continuous flow process.

[0070] To a 250 mL four-necked flask, add 30.0 g of N, N-dimethylethoxy-4-octylphenyl ether, 120.0 g of ethyl acetate and 12.10 g of benzyl chloride, stir and heat to 53-55 ° C for reaction, maintain for 24 hours, pass the control, cool to 10 ° C, filter, and rinse the filter cake with 50.0 g of ethyl acetate twice. The wet product is dried at 105 ° C for 2 hours. The dry weight is 33.4 g, the purity is 85.731%, and the yield is 73.3%.

[0071] The results of Example 2 and Comparative Example 3 are compared in Table 3.

[0072] Table 3

[0073] As shown in Table 3, the preparation of the crude benzethonium chloride product by the continuous flow process provided by S5 in the present invention can improve the yield of the crude benzethonium chloride product, and the purity of the crude benzethonium chloride product prepared is higher.

[0074] Comparative Example 4 Comparative Example 4 is compared with Example 1, except that more benzyl chloride is used, and the continuous flow process provided by S5 of the present invention is adopted to prepare the crude benzethonium chloride.

[0075] Add 30.0 g of N,N-dimethylethoxy-4-tert-octylphenyl ether into a 250 ml four-necked flask containing 120.0 g of ethyl acetate and stir at room temperature until dissolved.

[0076] The mixed solution and 30 g of benzyl chloride were pumped into the reaction flask using a metering pump. The reaction was maintained at 45°C for 16 hours. After the reaction was qualified, the temperature was lowered to 10°C and filtered. The filter cake was rinsed twice with 50.0 g of ethyl acetate. The wet product was dried at 105°C for 2 hours. The dry weight was 39.2 g, the purity was 96.147%, and the yield was 86.1%.

[0077] The results of Example 2 and Comparative Example 4 are compared in Table 4.

[0078] Table 4

[0079] As shown in Table 4, the continuous flow process provided by S5 in the present invention is used to prepare the crude benzethonium chloride. Under the premise of not affecting the purity and yield of the crude benzethonium chloride, the amount of benzyl chloride can be greatly reduced, thereby effectively reducing the raw material cost. Since a large amount of benzyl chloride takes longer to be pumped into the reactor, the production efficiency is also greatly improved.

[0080] Example 3 Example 3 The obtained crude benzethonium chloride was refined by the method provided in S6 of the present invention.

[0081] 600 g of ethyl acetate, 100 g of benzethonium chloride, and 30.0 g of anhydrous ethanol were added to the reactor in sequence, and the temperature was raised to 60-70 ° C to form a light yellow solution. 6.0 g of diatomaceous earth was added and stirred for 1.0 h. The mixture was filtered while hot (solids may precipitate during filtration, and the solids and liquids were transferred to the crystallization kettle together). The filtrate was heated to 70-75 ° C. The solution was a colorless transparent liquid. Heating was stopped, and the stirring speed was reduced to half of the original speed. The mixture was slowly cooled to 30 ° C by circulating water, and then cooled to 0-10 ° C with ice brine. The mixture was stirred for 1.5 h and centrifuged. The filter cake was fully washed with 120 g of ethyl acetate and dried to obtain 89.7 g of finished benzethonium chloride with a purity of 99.60% and a yield of 89.7%. The filtrate was retained for recovery of ethyl acetate.

[0082] While embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions, and variations may be made to these embodiments without departing from the principles and spirit of the invention, and that the scope of the invention is defined by the appended claims and their equivalents.

Claims

1. A method for continuously producing benzethonium chloride, characterized in that, Here are the steps: S1, at room temperature, 4-tert-octylphenol was dissolved in dichlorodiethyl ether to prepare a 4-tert-octylphenol-dichlorodiethyl ether mixed solution, and then the 4-tert-octylphenol-dichlorodiethyl ether mixed solution and a potassium hydroxide solution with a concentration of 10-80% were pumped into a reactor in a continuous flow method to carry out etherification reaction, and after water extraction and layering, the lower aqueous layer was separated, and the organic phase of the lower layer was washed twice; S2, after washing, desolventizing and recovering dichlorodiethyl ether to obtain 4-tert-octylphenoxyethoxyethyl chloride; S3, the 4-tert-octylphenoxyethoxyethyl chloride, dimethylamine aqueous solution and sodium hydroxide prepared in S2 are subjected to a substitution reaction in a high-pressure reactor to obtain a feed solution containing N,N-dimethylethoxy-4-tert-octylphenethyl ether; S4, cooling the feed solution obtained in S3 to below 35° C., standing to separate layers, taking the upper layer, washing it twice with a 5-40% sodium chloride aqueous solution at 40-50° C. to obtain an upper organic phase, and then distilling the upper organic phase under reduced pressure to remove water, thereby obtaining N,N-dimethylethoxy-p-tert-octylphenyl ether; S5. Stirring the N,N-dimethylethoxy-p-tert-octylphenyl ether and ethyl acetate prepared in S4 at room temperature until dissolved to obtain a N,N-dimethylethoxy-p-tert-octylphenyl ether-ethyl acetate mixture, and reacting the N,N-dimethylethoxy-p-tert-octylphenyl ether-ethyl acetate mixture with benzyl chloride in a continuous flow to obtain a crude benzethonium chloride product; S6, the benzethonium chloride crude product obtained in S5 is refined, ethyl acetate and anhydrous ethanol are heated and the benzethonium chloride crude product is dissolved and diatomaceous earth is added to stir, and hot filtration is carried out, and the filtrate is heated to be colorless transparent liquid and stops heating, slowly cools, filters, and fully washes with ethyl acetate, and oven dry namely obtains the benzethonium chloride finished product.

2. according to the method for a kind of continuous production benzethonium chloride of claim 1, it is characterized in that: In S1, the p-tert-octylphenol-dichlorodiethyl ether mixed solution and the potassium hydroxide solution are pumped into the reactor in a continuous flow method to carry out an etherification reaction. The reaction temperature is 60-120° C., the reaction time is 2.5 hours, and the flow rate ratio of the p-tert-octylphenol-dichlorodiethyl ether mixed solution to the potassium hydroxide solution is 1:(0.15-1.5).

3. according to the method for a kind of continuous production benzethonium chloride of claim 1, it is characterized in that: The mass ratio of p-tert-octylphenol, dichlorodiethyl ether and potassium hydroxide solution described in S1 is 1: (1.0-3.5): (0.1-1.0).

4. according to the method for a kind of continuous production of benzethonium chloride of claim 1, it is characterized in that: The reduced pressure desolventizing and recovering dichlorodiethyl ether in S2 adopts a vacuum degree of 15 mm Hg, a material temperature ≤ 160° C., and a top temperature ≤ 150° C.

5. according to the described method of a kind of continuous production benzethonium chloride of claim 1, it is characterized in that: In S3, 4-tert-octylphenoxyethoxyethyl chloride, dimethylamine aqueous solution and sodium hydroxide are subjected to substitution reaction in a high-pressure reactor at a reaction temperature of 110-120° C. and a pressure of 0.8-1.2 MPa for 6-12 hours.

6. according to the described method of a kind of continuous production benzethonium chloride of claim 1, it is characterized in that: The upper organic phase in S4 is subjected to reduced pressure distillation to remove water at -0.095 MPa, material temperature ≤ 120° C., and top temperature ≤ 100° C. to obtain N,N-dimethylethoxy-p-tert-octylphenyl ether.

7. A method for continuously producing benzethonium chloride according to claim 1, wherein: The mass ratio of 4-tert-octylphenoxyethoxyethyl chloride, dimethylamine aqueous solution, sodium hydroxide and sodium chloride in S3 and S4 is 1: (0.5-2.0): (0.05-1.0): (0.1-2.0).

8. A method for continuously producing benzethonium chloride according to claim 1, wherein: The N,N-dimethylethoxy-p-tert-octylphenyl ether-ethyl acetate mixture described in S5 is reacted with benzyl chloride in a continuous flow to form a salt to obtain a crude benzethonium chloride product. The reaction temperature is 30-75°C and the reaction time is 12-18 hours. The flow rate ratio of the N,N-dimethylethoxy-p-tert-octylphenyl ether-ethyl acetate mixture to the benzyl chloride is 1:(0.03-0.2).

9. A method for continuously producing benzethonium chloride according to claim 1, wherein: The mass ratio of N,N-dimethylethoxy-4-tert-octylphenyl ether, ethyl acetate and benzyl chloride in S5 is 1:(2.0-8.0):(0.1-1.0).

10. A method for continuously producing benzethonium chloride according to claim 1, characterized in that: The mass ratio of the crude benzethonium chloride, ethyl acetate, anhydrous ethanol and diatomaceous earth in S6 is 1: (2-8): (0.1-1): (0.01-1).

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