Device and method for producing paracetamol through acetylation of p-aminophenol by multiple serially connected kettles

Abstract

The invention provides a device and method for producing paracetamol through acetylation of p-aminophenol by multiple serially connected kettles.The device comprises a first-stage reaction kettle, a second-stage reaction kettle and a third-stage reaction kettle which are sequentially connected in series, a gas phase outlet in the top of each stage of reaction kettle is connected with a gas phase balance homogenizer, and an outlet of the gas phase balance homogenizer is connected with an inlet of a rectifying tower; a tower kettle outlet of the rectifying tower is connected with the first-stage reaction kettle. The gas phases of the reactors connected in series are connected through the gas phase balance homogenizer, and the rectifying tower is used for separating moisture in the gas phase reaction product, so that the p-aminophenol acetylation reaction is promoted to be carried out in the forward direction, unreacted acetic acid flows back to the reaction kettle for continuous reaction, the gas phases of the reactors can be balanced, and the yield of the p-aminophenol acetylation reaction is improved. The gas pressure and the gas flow of each stage of reaction are stable, the feeding gas flow of the rectifying tower is stable, the stability of continuous production is improved, the reaction conversion rate is high, the product yield is relatively high, and the industrial application prospect is relatively good.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical synthesis, and particularly relates to an apparatus and method for the acetylation of p-aminophenol in series of multiple reactors to produce paracetamol. Background Art

[0002] Paracetamol (p-acetamidophenol, APAP) is an organic compound and is the in vivo metabolite of phenacetin (acetophenetidin). In the 1870s, Harmon Northrop Morse first synthesized p-acetamidophenol by reacting p-nitrophenol with glacial acetic acid under the catalysis of tin. Pure paracetamol is a colorless crystalline powder with a melting point of 168 °C, soluble in solvents such as methanol and ethanol, and insoluble in solvents such as petroleum ether. The physical and chemical properties of paracetamol are relatively stable, and degradation may only occur after long-term exposure to heat and light.

[0003] Paracetamol is a common antipyretic and analgesic drug, originally used to replace antipyrine (acetanilide), mainly for treating diseases such as colds, fevers, and various pains. Due to its relatively low irritation to the stomach, good analgesic and antipyretic effects, and rapid onset of action, it has been widely used. In addition, compared with other common analgesic drugs such as aspirin and ibuprofen, it has a lower anti-inflammatory effect and is very suitable for those who cannot use non-steroidal anti-inflammatory drugs (NSAIDs).

[0004] The production of paracetamol mainly includes methods using hydroxyacetophenone and p-nitrophenol as raw materials. Hydroxyacetophenone reacts with hydroxylamine hydrochloride to obtain ketoxime, and then undergoes Beckmann rearrangement under the action of an acidic catalyst to obtain paracetamol, but the operation procedure of this method is relatively complex and a large amount of waste will be generated at the same time. A more common method is to catalyze p-nitrophenol to generate p-aminophenol, and then mix p-aminophenol with acetic acid and react under certain reaction conditions to generate paracetamol. Wiezer et al. optimized the reaction vessel from a fixed-bed reactor to a kettle reactor, so that the reaction can be carried out continuously, making the large-scale production of paracetamol possible.

[0005] Currently, the production method of paracetamol is mainly prepared by the acetylation reaction of p-aminophenol and acetic acid. However, with the continuous progress of the reaction, the generation of a large amount of water greatly restricts the reaction rate of the acetylation of p-aminophenol. If the water generated by the acetylation reaction of p-aminophenol cannot be removed in time, the yield of the final product paracetamol will be low. The traditional method of producing paracetamol intermittently using a single reactor cannot remove the water in time, which greatly restricts the acetylation reaction of p-aminophenol and results in low efficiency in producing the product paracetamol. Summary of the Invention

[0006] In order to improve the deficiencies of the above-mentioned existing production technologies, the present invention provides a device and method for acetylating p-aminophenol in series of multiple reactors to produce paracetamol. The gas phases of multiple reactors connected in series are connected through a gas-phase equilibrium homogenizer, which can not only timely remove the moisture in the reaction system, but also balance the gas phases of each reactor, making the gas pressure and gas flow of each stage of the reaction stable, and the feed gas flow of the distillation column stable, thereby improving the stability of continuous production.

[0007] To achieve the above object, the present invention adopts the following technical solutions:

[0008] A device for acetylating p-aminophenol in series of multiple reactors to produce paracetamol, comprising a first-stage reaction kettle 3, a second-stage reaction kettle 4 and a third-stage reaction kettle 5 connected in series in sequence. The top gas-phase outlets of the first-stage reaction kettle 3, the second-stage reaction kettle 4 and the third-stage reaction kettle 5 are connected to a gas-phase equilibrium homogenizer 6. The outlet of the gas-phase equilibrium homogenizer 6 is connected to the inlet of a distillation column 7. The bottom outlet of the distillation column 7 is connected to the first-stage reaction kettle 3 through a reflux pipe 701.

[0009] The gas-phase equilibrium homogenizer 6 has two functions. One is to balance the pressures of the three reaction kettles, and the other is to mix the gases from the three reaction kettles evenly to ensure the stability of the feed composition and flow rate of the distillation column.

[0010] Preferably, the first-stage reaction kettle 3 is connected to the second-stage reaction kettle 4 through a first overflow pipe 12, the second-stage reaction kettle 4 is connected to the third-stage reaction kettle 5 through a second overflow pipe 11, and the third-stage reaction kettle 5 overflows and discharges. The third-stage reaction kettle extracts the reaction product.

[0011] Preferably, a circulation outlet is provided at the bottom of the first-stage reaction kettle 3, the second-stage reaction kettle 4 or the third-stage reaction kettle 5. The circulation outlet is connected to a circulation inlet 10 provided in the same reaction kettle through a circulation pump 8. To achieve the single-kettle circulation of liquid materials.

[0012] Preferably, a vertical circulation conduit 9 is provided in the first-stage reaction kettle 3, the second-stage reaction kettle 4 or the third-stage reaction kettle 5, and the circulation inlet 10 is provided in the circulation conduit 9. To avoid affecting the overflow discharge.

[0013] The circulating pump is used to extract the liquid material from the bottom of its reaction kettle and circulate it to the circulating conduit 9 in the middle of the reaction kettle to achieve the mixing and stirring of the liquid material. The circulation flow rate is 6 - 30 m 3 / h.

[0014] Preferably, the gas-phase equilibrium homogenizer 6 includes a first inlet pipe 611, and a funnel-shaped second inlet chamber 612 and third inlet chamber 613. The inlet of the first inlet pipe 611 is connected to the first reactor 3, and the outlet of the first inlet pipe 611 is disposed inside the neck of the second inlet chamber 612. The neck opening of the second inlet chamber is disposed inside the neck of the third inlet chamber 613. The neck opening of the third inlet chamber 613 is the outlet of the gas-phase equilibrium homogenizer 6. The funnel part of the second inlet chamber 612 is provided with an inlet connected to the second reactor 4, and the funnel part of the third inlet chamber 613 is provided with an inlet connected to the third reactor 5. The gas-phase equilibrium homogenizer adopts a mode of a large pipe sleeving a small pipe, which can prevent the mixed gas from flowing back into the reactor.

[0015] Preferably, the overhead product outlet of the distillation column 7 is connected to a removal pipe 702.

[0016] Preferably, the number of trays of the distillation column 7 is 30, and the inlet of the distillation column 7 is disposed at the 14th tray.

[0017] Preferably, the device further includes a raw material mixer 1, and the raw material mixer 1 is connected to the inlet of the first-stage reactor 3.

[0018] Preferably, a heat exchanger 2 is further disposed between the raw material mixer 1 and the first-stage reactor 3.

[0019] Preferably, the volumes of the first-stage reactor, the second-stage reactor, and the third-stage reactor are all 5 m 3 .

[0020] In the present invention, the gas-phase reaction products of each stage of the reactor are mixed in the gas-phase equilibrium homogenizer and then introduced into the distillation column. The water in the gas-phase reaction products is separated by the distillation column, and the remaining substances are a mixture mainly composed of acetic acid. It is sent back to the first-stage tank reactor through the reflux pipe. By this way, the reaction rate of the acetylation of p-aminophenol is accelerated, the conversion rate of p-aminophenol is increased, the yield of the final product paracetamol is increased, and the continuous production of paracetamol is realized, having good industrial application prospects.

[0021] The basic chemical reaction of the present invention is:

[0022] .

[0023] The present invention also provides a method for producing paracetamol by acetylation of p-aminophenol in series of multiple reactors, including the following steps:

[0024] (1) Feed the mixture of p - aminophenol, water, and acetic acid into the first - stage reactor 3 of the device for the first - stage reaction. After that, successively feed the liquid reaction mixture into the second - stage reactor 4 and the third - stage reactor 5 for the second - stage reaction and the third - stage reaction respectively. The reaction temperatures of the first - stage reaction, the second - stage reaction, and the third - stage reaction increase step by step.

[0025] (2) Mix the gas - phase products of the first - stage reactor 3, the second - stage reactor 4, and the third - stage reactor 5 in a gas - phase equilibrium homogenizer, and then feed them into the rectification column 7 for rectification. Feed the solution obtained at the bottom of the rectification column 7 into the first - stage reactor 3 through the reflux pipe 10.

[0026] Preferably, the pressure in the first - stage reactor 3, the second - stage reactor 4, and the third - stage reactor 5 is 1.01 bar.

[0027] Preferably, in step (1), the increasing range of the reaction temperature step by step is 2 - 10 °C.

[0028] Preferably, in step (1), the temperature of the first - stage reaction is 108 - 115 °C; the temperature of the second - stage reaction is 115 - 120 °C; the temperature of the third - stage reaction is 120 - 126 °C.

[0029] Preferably, in step (1), the reaction time of the first - stage reaction, the second - stage reaction, and the third - stage reaction is 6 h.

[0030] In the present invention, the unreacted acetic acid in the first - stage reactor, the second - stage reactor, and the third - stage reactor is recovered through the rectification column and fed into the first - stage reactor through the reflux pipe to continue the reaction. This can not only promote the forward progress of the acetylation reaction of p - aminophenol but also improve the conversion rate of p - aminophenol and the yield of the product paracetamol.

[0031] The final result shows that the overall conversion rate of p - aminophenol reaches 99.5%, and the overall yield of the product paracetamol exceeds 99.5%.

[0032] The device of the present invention can maximize the utilization of reaction raw materials, not only improving the conversion rate of p - aminophenol but also increasing the reaction rate of the acetylation of p - aminophenol.

[0033] The working principle and advantages of the present invention are as follows:

[0034] (1) The present invention provides a method and device for the acetylation of p - aminophenol to produce paracetamol by multi - kettle series connection. Through the way of three - kettle series reaction, the conversion rate of p - aminophenol is increased to 99.5%, and at the same time, the occurrence of side reactions can be inhibited.

[0035] (2) The present invention provides a method and apparatus for acetylating p-aminophenol in a series of multiple reactors to produce paracetamol. By means of a three-reactor series reaction and by gradually increasing the temperature of the reactors, the conversion rate of the raw materials is increased to more than 99.5%.

[0036] (3) The present invention provides a method and apparatus for acetylating p-aminophenol in a series of multiple reactors to produce paracetamol. The gas-phase products of each stage of the reactors are mixed together, and a distillation column is used to separate water from the reaction products, which can promote the forward progress of the p-aminophenol acetylation reaction.

[0037] (4) The present invention provides a method and apparatus for acetylating p-aminophenol in a series of multiple reactors to produce paracetamol. By combining a series of multiple reaction vessels with a distillation column, water in the gas-phase reaction product mixture is separated, and at the same time, the separated acetic acid can be used as a raw material to continue the p-aminophenol acetylation reaction, ultimately achieving the effect of "1 + 1 > 2".

[0038] (5) The present invention provides a method and apparatus for acetylating p-aminophenol in a series of multiple reactors to produce paracetamol. Under the reaction conditions of a relatively small acetic acid flow rate, a relatively high conversion rate of p-aminophenol can also be achieved, which has better economic benefits.

[0039] (6) In the present invention, the gas phases of a series of multiple reactors are connected through a gas-phase equilibrium homogenizer, which can not only timely remove moisture from the reaction system but also balance the gas phases of each reactor, making the gas pressure and gas flow of each stage of the reaction stable, the feed gas flow of the distillation column stable, and improving the stability of continuous production. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] The following further explains the present invention in conjunction with the drawings and specific embodiments.

[0041] Figure 1 is a schematic diagram of the apparatus for acetylating p-aminophenol in a series of multiple reactors according to the present invention.

[0042] Figure 2 is a schematic diagram of the structure of the gas-phase equilibrium homogenizer.

[0043] Among them, 1 is a raw material liquid mixer, 2 is a heat exchanger, 3 is a first-stage reactor, 4 is a second-stage reactor, 5 is a third-stage reactor, 6 is a gas-phase equilibrium homogenizer, 7 is a distillation column, 8 is a circulation pump, 9 is a circulation conduit, 10 is a circulation inlet, 11 is a second overflow pipe, 12 is a first overflow pipe. 701 is a reflux pipe, 601, 602, and 603 are all gas-phase output pipelines, 611 is a first intake pipe, 612 is a second intake cavity, 613 is a third intake cavity, and 702 is a removal pipeline. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0044] The technical solutions of the present invention will be described and demonstrated in detail below in combination with specific embodiments of the present invention. The embodiments described below are only partial embodiments of the present invention, not all embodiments. Based on the technical solutions and embodiments of the present invention, any other specific embodiments proposed without creative labor fall within the protection scope of the present invention.

[0045] As Figures 1-2 shown, a device for the acetylation of p-aminophenol in a multi-kettle series to produce paracetamol includes a first-stage reaction kettle 3, a second-stage reaction kettle 4, and a third-stage reaction kettle 5 connected in series in sequence. The top gas-phase outlets of the first-stage reaction kettle 3, the second-stage reaction kettle 4, and the third-stage reaction kettle 5 are connected to a gas-phase equilibrium homogenizer 6. The outlet of the gas-phase equilibrium homogenizer 6 is connected to the inlet of a rectification column 7. The bottom outlet of the rectification column 7 is connected to the inlet of the first-stage reaction kettle 3 through a reflux pipe 10.

[0046] The top product outlet of the rectification column 7 is connected to a removal pipeline.

[0047] The rectification column 7 has 30 trays, and the inlet of the rectification column 7 is arranged at the 14th tray.

[0048] The device further includes a raw material mixer 1, and the raw material mixer 1 is connected to the inlet of the first-stage reaction kettle 3.

[0049] A heat exchanger 2 is further arranged between the raw material mixer 1 and the first-stage reaction kettle 3.

[0050] The volumes of the first-stage reaction kettle, the second-stage reaction kettle, and the third-stage reaction kettle are all 5 m 3 .

[0051] Example 1

[0052] Using the above device:

[0053] (1) Acetic acid, p-aminophenol, and water are first mixed together at a flow rate of 1217.3 kg / h, 1639.2 kg / h, and 979.6 kg / h respectively, and are heated to a certain temperature by a heat exchanger, and then continuously introduced into the first-stage reaction kettle. The volume of the first-stage reaction kettle is 5 m 3 , the reaction pressure is 1.01 bar, and the first acetylation reaction of p-aminophenol is carried out at a temperature of 115 °C to obtain a first gas-phase product and a first liquid-phase product.

[0054] (2) The obtained first liquid-phase product is introduced into the second-stage reaction kettle. The volume of the second-stage reaction kettle is 5 m 3, the reaction pressure was 1.01 bar, and the second acetylation reaction of p-aminophenol was carried out at a temperature of 120 °C to obtain a second gas-phase product and a second liquid-phase product.

[0055] (3) The obtained second liquid-phase product was introduced into the third-stage reactor. The volume of the third-stage reactor was 5 m 3 , the reaction pressure was 1.01 bar, and the third acetylation reaction of p-aminophenol was carried out at a temperature of 125 °C to obtain a third gas-phase product and a third liquid-phase product.

[0056] (4) The first gas-phase product, the second gas-phase product, and the third gas-phase product were mixed together through a gas-phase equilibrium homogenizer and then introduced into a rectification separation column. The water in the gas-phase reaction product mixture was separated by the rectification column.

[0057] (5) The main component separated from the bottom of the rectification column was acetic acid that had not reacted completely in the previous-stage reactors. At this time, the purity of acetic acid was still very high and could be used as a reaction raw material. Through the provided reflux pipe, the liquid at the bottom of the rectification column was introduced into the first-stage reactor to continue the acetylation reaction of p-aminophenol therein.

[0058] Among them, a mixture solution of p-aminophenol, acetic acid, and water was continuously introduced into the first-stage reactor at 3836.1 kg / h. The gas-phase reaction product mixture obtained through the reaction in the three-stage series reactors was introduced into the rectification column, and the water in it was separated.

[0059] The results were as follows:

[0060] (1) In the first-stage reactor, the first liquid-phase product obtained through the first acetylation reaction of p-aminophenol was continuously introduced into the second-stage reactor to continue the second acetylation reaction of p-aminophenol therein.

[0061] (2) In the second-stage reactor, the second liquid-phase product obtained through the second acetylation reaction of p-aminophenol was continuously introduced into the third-stage reactor to continue the third acetylation reaction of p-aminophenol therein.

[0062] (3) The gas-phase reaction product mixture of the three acetylation reactions of p-aminophenol was introduced into the rectification column, the water in it was separated, and the obtained acetic acid was introduced into the first-stage reactor to continue the acetylation reaction of p-aminophenol.

[0063] (4) The recovery rate of acetic acid in the gas-phase reaction product was 94.2%, the conversion rates of p-aminophenol were 81.5%, 96.5%, and 99.5% respectively, the overall yield of paracetamol was 99.47%, and the final product paracetamol was continuously withdrawn from the third-stage reactor.

[0064] Example 2

[0065] The main difference between this embodiment and Embodiment 1 is that in this embodiment, the reaction temperature in the first-stage reactor is 115 °C, the reaction temperature in the second-stage reactor is 117 °C, and the reaction temperature in the third-stage reactor is 119 °C.

[0066] The results are as follows:

[0067] (1) In the first-stage reactor, the first liquid-phase product obtained through the first acetylation reaction of p-aminophenol is continuously fed into the second-stage reactor, where the second acetylation reaction of p-aminophenol continues.

[0068] (2) In the second-stage reactor, the second liquid-phase product obtained through the second acetylation reaction of p-aminophenol is continuously fed into the third-stage reactor, where the third acetylation reaction of p-aminophenol continues.

[0069] (3) The gas-phase reaction product mixture of the three acetylation reactions of p-aminophenol is fed into a distillation column, where the water is separated out, and the acetic acid obtained is fed into the first-stage reactor to continue the acetylation reaction of p-aminophenol.

[0070] (4) The recovery rate of acetic acid in the gas-phase reaction product is 79.64%, the conversion rates of p-aminophenol are 81.5%, 95.9%, and 99.1% respectively, the overall yield of paracetamol is 99.12%, and the final product paracetamol is continuously withdrawn from the third-stage reactor.

[0071] Embodiment 3

[0072] The main difference between this embodiment and Embodiment 1 is that in this embodiment, the reaction temperature in the first-stage reactor is 115 °C, the reaction temperature in the second-stage reactor is 123 °C, and the reaction temperature in the third-stage reactor is 131 °C.

[0073] The results are as follows:

[0074] (1) In the first-stage reactor, the first liquid-phase product obtained through the first acetylation reaction of p-aminophenol is continuously fed into the second-stage reactor, where the second acetylation reaction of p-aminophenol continues.

[0075] (2) In the second-stage reactor, the second liquid-phase product obtained through the second acetylation reaction of p-aminophenol is continuously fed into the third-stage reactor, where the third acetylation reaction of p-aminophenol continues.

[0076] (3) The gas-phase reaction product mixture of the three acetylation reactions of p-aminophenol is fed into a distillation column, where the water is separated out, and the acetic acid obtained is fed into the first-stage reactor to continue the acetylation reaction of p-aminophenol.

[0077] (4) The recovery rate of acetic acid in the gas-phase reaction product is 95.4%, the conversion rates of p-aminophenol are 81.5%, 97.0%, and 99.7% respectively, and the overall yield of paracetamol is 99.7%. The final product paracetamol is continuously withdrawn from the third reaction kettle.

[0078] Example 4

[0079] The main difference between this example and Example 1 is that the ratio of the raw materials acetic acid and p-aminophenol added in this example is 1.5:1.

[0080] The results are as follows:

[0081] (1) In the first reaction kettle, the first liquid-phase product obtained through the first acetylation reaction of p-aminophenol is continuously introduced into the second reaction kettle, where the second acetylation reaction of p-aminophenol continues.

[0082] (2) In the second reaction kettle, the second liquid-phase product obtained through the second acetylation reaction of p-aminophenol is continuously introduced into the third reaction kettle, where the third acetylation reaction of p-aminophenol continues.

[0083] (3) The gas-phase reaction product mixture of the three acetylation reactions of p-aminophenol is introduced into a distillation column, and the water therein is separated. The obtained acetic acid is introduced into the first reaction kettle to continue the acetylation reaction of p-aminophenol.

[0084] (4) The recovery rate of acetic acid in the gas-phase reaction product is 94.1%, the final conversion rate of p-aminophenol is 99.4%, and the overall yield of paracetamol is 99.47%. The final product paracetamol is continuously withdrawn from the third reaction kettle.

[0085] Example 5

[0086] The main difference between this example and Example 1 is that the ratio of the raw materials acetic acid and p-aminophenol added in this example is 1.6:1.

[0087] The results are as follows:

[0088] (1) In the first reaction kettle, the first liquid-phase product obtained through the first acetylation reaction of p-aminophenol is continuously introduced into the second reaction kettle, where the second acetylation reaction of p-aminophenol continues.

[0089] (2) In the second reaction kettle, the second liquid-phase product obtained through the second acetylation reaction of p-aminophenol is continuously introduced into the third reaction kettle, where the third acetylation reaction of p-aminophenol continues.

[0090] (3)The gas-phase reaction product mixture of the three-time acetylation reaction of p-aminophenol is introduced into a distillation column, and the water therein is separated out. The acetic acid obtained is introduced into the first-stage reactor to continue the acetylation reaction of p-aminophenol.

[0091] (4)The recovery rate of acetic acid in the gas-phase reaction product is 94.2%, the final conversion rate of p-aminophenol is 99.5%, and the overall yield of paracetamol is 99.47%. The final product paracetamol is continuously withdrawn from the third-stage reactor.

[0092] Comparative Example 1

[0093] This comparative example is a process method for the acetylation of p-aminophenol in series of multiple reactors to produce paracetamol, which specifically includes the following steps:

[0094] (1)Acetic acid is first mixed with p-aminophenol and water at a flow rate of 1217.3 kg / h, 1639.2 kg / h, and 979.6 kg / h respectively, and then heated to a certain temperature by a heat exchanger, and then continuously introduced into the first-stage reactor. The volume of the reactor is 5 m 3 , the reaction pressure is 1.01 bar, and the first acetylation reaction of p-aminophenol is carried out at a temperature of 115 °C to obtain a first gas-phase product and a first liquid-phase product. The first gas-phase product is sent to a distillation column for rectification to recover acetic acid.

[0095] (2)The obtained first liquid-phase product is introduced into the second-stage reactor. The volume of the reactor is 5 m 3 , the reaction pressure is 1.01 bar, and the second acetylation reaction of p-aminophenol is carried out at a temperature of 120 °C to obtain a second gas-phase product and a second liquid-phase product. The second gas-phase product is sent to the first-stage reactor.

[0096] (3)The obtained second liquid-phase product is introduced into the third-stage reactor. The volume of the reactor is 5 m 3 , the reaction pressure is 1.01 bar, and the third acetylation reaction of p-aminophenol is carried out at a temperature of 125 °C to obtain a third gas-phase product and a third liquid-phase product. The third gas-phase product is sent to the second-stage reactor.

[0097] Among them, the mixture solution of p-aminophenol, acetic acid, and water is continuously introduced into the first-stage reactor at a rate of 3836.1 kg / h for the acetylation reaction of p-aminophenol.

[0098] The results are as follows:

[0099] (1)The final product paracetamol is continuously withdrawn from the liquid-phase product obtained in the third-stage reactor. The final conversion rate of p-aminophenol is 93.7%, and the overall yield of paracetamol is 93.7%.

[0100] (2) Rectification column section, the recovery rate of acetic acid is 80.6%,

[0101] Comparative Example 2

[0102] This comparative example is a process for the acetylation of p-aminophenol to produce paracetamol, which specifically includes the following steps:

[0103] Mix acetic acid at a flow rate of 2000.0 kg / h, p-aminophenol at a flow rate of 1640.0 kg / h and water at a flow rate of 980.0 kg / h together first, heat them to a certain temperature condition through a heat exchanger, and then continuously feed them into a kettle reactor. The volume of the reaction kettle is 5 m 3 , the reaction pressure is 1.01 bar, and the acetylation reaction of p-aminophenol is carried out at a temperature of 115 °C to obtain a gas-phase product and a liquid-phase product. The product paracetamol is continuously withdrawn from the liquid-phase product.

[0104] Among them, a mixture solution of p-aminophenol, acetic acid and water is continuously fed into the reaction kettle at a rate of 4620.0 kg / h for the acetylation reaction of p-aminophenol.

[0105] The result is:

[0106] The final product paracetamol is continuously withdrawn from the liquid-phase product obtained by the reaction. The conversion rate of p-aminophenol is 81.5%, and the final yield of paracetamol is 81.5%.

[0107] Comparative Example 3

[0108] This comparative example is a process for the acetylation of p-aminophenol in series of multiple kettles to produce paracetamol, which specifically includes the following steps:

[0109] (1) Mix acetic acid at a flow rate of 1371.8 kg / h, p-aminophenol at a flow rate of 1639.3 kg / h and water at a flow rate of 942.8 kg / h together first, use a heat exchanger to make it reach a certain temperature, and then continuously feed it into the first-stage reaction kettle. The volume of the first-stage reaction kettle is 5 m 3 , the reaction pressure is 1.01 bar, and the first acetylation reaction of p-aminophenol is carried out at a temperature of 115 °C to obtain a first gas-phase product and a first liquid-phase product.

[0110] (2) Feed the obtained first liquid-phase product into the second-stage reaction kettle. The volume of the second-stage reaction kettle is 5 m 3 , the reaction pressure is 1.01 bar, and the second acetylation reaction of p-aminophenol is carried out at a temperature of 115 °C to obtain a second gas-phase product and a second liquid-phase product.

[0111] (3) Feed the obtained second liquid-phase product into the third-stage reactor. The volume of the third-stage reactor is 5 m 3 , the reaction pressure is 1.01 bar, and the third acetylation reaction of p-aminophenol is carried out at a temperature of 115 °C to obtain a third gas-phase product and a third liquid-phase product.

[0112] (4) Mix the first gas-phase product, the second gas-phase product, and the third gas-phase product together through a gas-phase equilibrium homogenizer, and then feed them into a rectification separation column. Use the rectification column to separate the water in the gas-phase reaction product mixture.

[0113] (5) The substances in the bottom of the rectification column are mainly acetic acid that has not reacted completely in the previous-stage reactors. Through the acetic acid circulation pipeline, the bottom liquid is fed into the first-stage reactor to continue the acetylation reaction of p-aminophenol therein.

[0114] Among them, the mixture solution of p-aminophenol, acetic acid, and water is continuously fed into the first-stage reactor at 3953.9 kg / h; the gas-phase reaction product mixture obtained through the reaction in the three-stage series reactors is fed into the rectification column to separate the water therein.

[0115] The results are as follows:

[0116] (1) After the first acetylation reaction of p-aminophenol, the obtained first liquid-phase product is continuously fed into the second-stage reactor to continue the acetylation reaction of p-aminophenol.

[0117] (2) After the second acetylation reaction of p-aminophenol, the obtained second liquid-phase product is continuously fed into the third-stage reactor to continue the acetylation reaction of p-aminophenol.

[0118] (3) The gas-phase reaction product mixture of the three acetylation reactions of p-aminophenol is fed into the rectification column to separate the water therein, and the obtained acetic acid is fed into the first-stage reactor to continue the reaction.

[0119] (4) The recovery rate of acetic acid in the gas-phase reaction product is 95.4%, the conversion rates of p-aminophenol are 81.5%, 95.4%, and 98.7% respectively, and the overall yield of paracetamol is 98.76%. The final product paracetamol is continuously withdrawn from the third-stage reactor.

[0120] Comparative Example 4

[0121] This comparative example is a process for producing paracetamol by the acetylation of p-aminophenol in a multi-reactor series, which specifically includes the following steps:

[0122] The main difference between this comparative example and Comparative Example 3 is that in this comparative example, the reaction temperature in the first-stage reactor is 120 °C, the reaction temperature in the second-stage reactor is 120 °C, and the reaction temperature in the third-stage reactor is 120 °C.

[0123] The results are as follows:

[0124] The recovery rate of acetic acid in the gas-phase reaction product is 84.1%, the conversion rates of p-aminophenol are 85.2%, 96.8%, and 99.2% respectively, the overall yield of paracetamol is 99.25%, and the final product paracetamol is continuously withdrawn from the third-stage reactor.

[0125] Comparative Example 5

[0126] This comparative example is a process for the acetylation of p-aminophenol in series of multiple reactors to produce paracetamol, which specifically includes the following steps:

[0127] The main difference between this comparative example and Comparative Example 3 is that in this comparative example, the reaction temperature in the first-stage reactor is 125 °C, the reaction temperature in the second-stage reactor is 125 °C, and the reaction temperature in the third-stage reactor is 125 °C.

[0128] The results are as follows:

[0129] The recovery rate of acetic acid in the gas-phase reaction product is 94.2%, the conversion rates of p-aminophenol are 88.1%, 97.8%, and 99.5% respectively, the overall yield of paracetamol is 99.57%, and the final product paracetamol is continuously withdrawn from the third-stage reactor.

[0130] From the results of the above examples and comparative examples, it can be seen that the method of combining series of multiple reactors with a distillation column provided by the present invention can effectively improve the conversion rate of p-aminophenol and further increase the yield of the product paracetamol compared with a single-reactor device and a series of multiple reactors without using a distillation column. At the same time, the method provided by the present invention can realize the industrial continuous production of paracetamol, shorten the reaction time, and has good industrial application value.

[0131] It can also be seen from the results of the examples that the present invention conducts the acetylation reaction of p-aminophenol in multiple steps in a series of multiple reactors, and the temperature in each stage of the reactor needs to be gradually increased to make the method play a greater role, and finally the conversion rate of p-aminophenol and the yield of the product paracetamol are improved.

[0132] The method combining a rectification column with a series connection of multiple reactors provided by the present invention can remove water in the acetic acid product, enabling the acetylation reaction of p-aminophenol to proceed in the forward direction, improving the reaction conversion rate. At the same time, the recovered acetic acid can still be used as a reaction raw material and introduced into the first-stage reactor to continue the acetylation reaction of p-aminophenol, which can save raw materials and improve the reaction conversion rate at the same time.

[0133] The above are only some specific embodiments of the present invention and cannot limit the present invention. Any simple substitution, improvement, etc. made without creative changes based on the basic principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A device for producing paracetamol by acetylation of p-aminophenol in multiple reactors in series, characterized in that: The invention comprises a first-stage reactor (3), a second-stage reactor (4) and a third-stage reactor (5) which are connected in series in sequence, wherein the top gas phase outlets of the first-stage reactor (3), the second-stage reactor (4) and the third-stage reactor (5) are connected to a gas phase equilibrium homogenizer (6), the outlet of the gas phase equilibrium homogenizer (6) is connected to the inlet of a distillation tower (7), and the tower bottom outlet of the distillation tower (7) is connected to the first-stage reactor (3) via a reflux pipe (701).

2. The device according to claim 1, characterized in that The first-stage reactor (3) is connected to the second-stage reactor (4) via a first overflow pipe (12), the second-stage reactor (4) is connected to the third-stage reactor (5) via a second overflow pipe (11), and the third-stage reactor (5) discharges material by overflow.

3. The device according to claim 1, characterized in that A circulation outlet is provided at the bottom of the first-stage reactor (3), the second-stage reactor (4) or the third-stage reactor (5), and the circulation outlet is connected to a circulation inlet (10) provided in the same reactor via a circulation pump (8); preferably, a vertical circulation conduit (9) is provided in the first-stage reactor (3), the second-stage reactor (4) or the third-stage reactor (5), and the circulation inlet (10) is provided in the circulation conduit (9).

4. The device according to claim 1, characterized in that The gas phase equilibrium homogenizer (6) comprises a first air inlet pipe (611) and a second funnel-shaped air inlet chamber (612) and a third air inlet chamber (613); the inlet of the first air inlet pipe (611) is connected to the first reactor (3); the outlet of the first air inlet pipe (611) is arranged in the neck of the second air inlet chamber (612); the neck of the second air inlet chamber is arranged in the neck of the third air inlet chamber (613); the neck of the third air inlet chamber (613) is the outlet of the gas phase equilibrium homogenizer (6); the inlet of the funnel portion of the second air inlet chamber (612) is connected to the second reactor (4); the inlet of the funnel portion of the third air inlet chamber (613) is connected to the third reactor (5).

5. The device according to claim 1, characterized in that The distillation tower (7) has 30 plates, and the inlet of the distillation tower (7) is arranged at the 14th plate.

6. The device according to claim 1, characterized in that The device further comprises a raw material mixer (1), wherein the raw material mixer (1) is connected to the inlet of the first-stage reaction kettle (3).

7. The device according to claim 1, characterized in that A heat exchanger (2) is also provided between the raw material mixer (1) and the first-stage reaction kettle (3).

8. A method for producing paracetamol by acetylation of p-aminophenol in multiple reactors in series, characterized in that: The steps include: (1) feeding a mixture of p-aminophenol, water and acetic acid into a first-stage reactor of the device to carry out a first-stage reaction, and then feeding the liquid reaction mixture into a second-stage reactor and a third-stage reactor in sequence to carry out a second-stage reaction and a third-stage reaction in sequence, wherein the reaction temperatures of the first-stage reaction, the second-stage reaction and the third-stage reaction are increased step by step; (2) The gaseous products of the first-stage reactor, the second-stage reactor and the third-stage reactor are mixed in a gas phase equilibrium homogenizer and then sent to the distillation tower for distillation, and the solution obtained in the bottom of the distillation tower is sent to the first-stage reactor through the reflux pipe.

9. The method according to claim 8, characterized in that The pressure in the first-stage reactor, the second-stage reactor and the third-stage reactor is 1.01 bar.

10. The method according to claim 8, characterized in that The reaction temperature in step (1) is gradually increased by 2-10°C; preferably, the temperature of the first-stage reaction is 108-115°C; the temperature of the second-stage reaction is 115-120°C; and the temperature of the third-stage reaction is 120-126°C.

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