Multi-stage continuous cooling crystallization device and method for acetaminophen

Abstract

The invention relates to the technical field of acetaminophen crystallization, in particular to a multi-stage continuous cooling crystallization device and method for acetaminophen. The invention provides a multi-stage continuous cooling crystallization method for acetaminophen, which comprises the following steps: S1, at least five stages of continuous cooling crystallization are adopted, and circulating water with a set temperature is injected into a jacket of a crystallization kettle during each stage of cooling crystallization; wherein during the first several stages of crystallization, the difference between the initial temperature of the material entering the crystallization kettle and the initial temperature of the circulating water is 13-25 DEG C; and during the last crystallization, the initial temperature of the material entering the crystallization kettle is 30-35 DEG C. According to the multi-stage continuous cooling crystallization method, different water temperatures are adopted to carry out gradient cooling on the materials, so that the problems of non-uniform grain size and low purity caused by crystal explosion due to large temperature difference between the materials and a refrigerant and high cooling rate in the early stage of cooling are avoided.

Description

Technical Field

[0001] The present invention relates to the technical field of acetaminophen crystallization, and in particular to a multi-stage continuous cooling crystallization device and method for acetaminophen. Background Art

[0002] Para-aminophenol and Glacial acetic acid are added to acylation kettle after the batching of the batching container, and acylation is carried out at 140 ℃, and after acylation is finished, the acylation material needs to be carried out crystallization. At present, after para-aminophenol and Glacial acetic acid carry out acylation acid steaming and finish, can directly carry out decrease temperature crystallization in acylation tank, and then in addition centrifugation, but if the time of taking acylation tank will increase in that case, this will affect the carrying out of the acylation reaction of next batch of materials, in order to accelerate the circulation process of material, improve output, so select two jars to carry out acylation and crystallization respectively. Promptly in order not to take acylation tank resource, after acylation reaction and acid steaming process are finished, acylation acid steaming is finished and the back gained feed liquid (hereinafter referred to as acylation feed liquid) is put into another crystallization kettle and carries out crystallization reaction.

[0003] During crystallization, circulating water at a fixed temperature is usually introduced into the jacket of the crystallizer for cooling. The water temperature is relatively low (15-30°C). In the early stage of cooling, due to the large temperature difference between the material and the refrigerant, the cooling rate is fast, resulting in crystal explosion and the formation of many small crystal particles. This causes uneven grain size, low grain purity, poor quality, and scaling of the crystallizer. If water of different temperatures is used for cooling (such as 90°C in the early stage, 70°C in the middle stage, then down to 50°C, and finally 30°C), the alternating hot and cold temperatures will damage the crystallizer, shorten its service life, and make the operation more cumbersome. Summary of the Invention

[0004] The problem to be solved by the present invention is that, in the past, circulating water at a fixed temperature was typically introduced into the jacket of the crystallizer for cooling. This low water temperature resulted in a large temperature difference between the material and the refrigerant in the early stages of cooling, leading to a rapid cooling rate and a burst of crystals. This resulted in a large number of small crystals, resulting in uneven grain size, low grain purity, poor quality, and scaling in the crystallizer. If water of different temperatures were used for cooling, alternating hot and cold cycles would damage the crystallizer, shorten its service life, and be more cumbersome to operate.

[0005] Technical Solution

[0006] A multi-stage continuous cooling crystallization method for acetaminophen comprises the following steps:

[0007] S1: Perform at least five stages of continuous cooling crystallization, and inject circulating water of a set temperature into the jacket of the crystallization kettle during each stage of cooling crystallization; wherein:

[0008] During the first few stages of crystallization, the difference between the initial temperature of the material entering the crystallization kettle and the initial temperature of the circulating water is 13°C-25°C;

[0009] During the last crystallization, the initial temperature of the material entering the crystallization kettle is 30°C-35°C, and the difference between the initial temperature of the material entering the crystallization kettle and the initial temperature of the circulating water is 21°C-28°C;

[0010] S2: Open the transfer pumps between the crystallization kettles in sequence according to the set time.

[0011] According to one embodiment of the present invention, step S1 further includes: turning on the spiral agitator 7 in each crystallization kettle.

[0012] According to one embodiment of the present invention, in step S1, five-stage continuous cooling crystallization is adopted, which specifically includes:

[0013] During the first stage crystallization, the initial temperature of the material entering the first stage crystallization kettle 8 is 110°C, and the initial temperature of the circulating water in the jacket of the first stage crystallization kettle 8 is 90°C-92°C;

[0014] During the second stage crystallization, the initial temperature of the material entering the secondary crystallization kettle 14 is 95° C., and the initial temperature of the circulating water in the jacket of the secondary crystallization kettle 14 is 70° C.-72° C.;

[0015] During the third stage crystallization, the initial temperature of the material entering the third stage crystallization kettle 20 is 75°C, and the initial temperature of the circulating water in the jacket of the third stage crystallization kettle 20 is 50°C-52°C;

[0016] During the fourth stage crystallization, the initial temperature of the material entering the fourth stage crystallization kettle 24 is 55°C, and the initial temperature of the circulating water in the jacket of the fourth stage crystallization kettle 24 is 30°C-32°C;

[0017] During the fifth stage crystallization, the initial temperature of the material entering the fifth stage crystallization kettle 28 is 35°C, and the initial temperature of the circulating water in the jacket of the fifth stage crystallization kettle 28 is 7°C-9°C.

[0018] A multi-stage continuous cooling crystallization device for acetaminophen is used to implement the above-mentioned multi-stage continuous cooling crystallization method. The multi-stage continuous cooling crystallization device for acetaminophen includes a plurality of crystallization kettles and a heat exchange mechanism corresponding to each crystallization kettle; a material conveying mechanism for conveying material is installed between any two adjacent crystallization kettles; the crystallization kettle includes a kettle body and a jacket provided on the outside of the kettle body, and the jacket is provided with a condensed water inlet and a condensed water outlet;

[0019] Each of the crystallization kettles is equipped with a corresponding heat exchange mechanism, which is used to exchange heat with the material in the corresponding crystallization kettle to reduce the temperature of the material; the heat exchange mechanism includes a circulating water pump and a circulating water insulation kettle, the water inlet of the circulating water pump is connected to the water outlet of the circulating water insulation kettle, the water outlet of the circulating water pump is connected to the condensed water inlet on the jacket, and the circulating water insulation kettle is connected to the condensed water outlet on the jacket through a pipeline; the circulating water pump is used to extract the circulating water in the circulating water insulation kettle and inject it into the jacket of the crystallization kettle.

[0020] According to one embodiment of the present invention, the heat exchange mechanism includes a circulating water heat exchanger, the water inlet of the circulating water heat exchanger is connected to the condensed water outlet on the crystallization kettle, and the water outlet of the circulating water heat exchanger is connected to the circulating water insulation kettle.

[0021] According to one embodiment of the present invention, an acylation pump and a five-stage transfer pump are included; there are five crystallization kettles, and the five crystallization kettles include a first-stage crystallization kettle, a second-stage crystallization kettle, a third-stage crystallization kettle, a fourth-stage crystallization kettle and a fifth-stage crystallization kettle;

[0022] The feed port of the acylation pump is connected to the discharge port of the acylation kettle through a pipeline, and the discharge port of the acylation pump is connected to the feed port of the primary crystallization kettle through a pipeline;

[0023] The feed port of the five-stage transfer pump is connected to the discharge port of the five-stage crystallization kettle through a pipeline, and the discharge port of the five-stage transfer pump is connected to the feed port of the centrifuge through a pipeline.

[0024] According to one embodiment of the present invention, the crystallization kettle comprises a primary heat exchanger and a primary reflux detector, wherein the primary crystallization kettle and the primary heat exchanger are connected via a pipeline, and the primary reflux detector is installed on the pipeline between the primary crystallization kettle and the primary heat exchanger;

[0025] The primary heat exchanger is used for condensing the mixed steam of water and glacial acetic acid.

[0026] According to one embodiment of the present invention, it includes a secondary heat exchanger and a secondary reflux detector, the secondary crystallization kettle and the secondary heat exchanger are connected by a pipeline, and the secondary reflux detector is installed on the pipeline between the secondary crystallization kettle and the secondary heat exchanger.

[0027] According to one embodiment of the present invention, a plurality of baffles are installed on the inner wall of each crystallization kettle, and the baffles are evenly arranged around the inner wall of the crystallization kettle.

[0028] According to one embodiment of the present invention, the material conveying mechanism includes a transfer pump, a first pipe and a second pipe, one end of the first pipe is connected to the discharge port of a crystallization kettle, and the other end thereof is connected to the feed port of the transfer pump, and one end of the second pipe is connected to the discharge port of the transfer pump, and the other end thereof is connected to the feed port of another crystallization kettle.

[0029] Beneficial effects of the present invention:

[0030] In this multi-stage continuous cooling crystallization method, different water temperatures are used to perform gradient cooling on the material, thereby avoiding the problems of uneven grain size, low grain purity and poor quality caused by the crystal explosion caused by the large temperature difference between the material and the refrigerant and the fast cooling rate in the early stage of cooling. Moreover, since the circulating water temperature of each stage of the crystallization kettle is constant, there is no need to frequently change water of different temperatures, thus avoiding damage to the crystallization kettle due to alternating hot and cold. In addition, since the difference between the initial temperature of the material entering the crystallization kettle and the initial temperature of the circulating water entering the jacket of the crystallization kettle is small, it will not cause a sudden drop in local temperature to form a local supersaturated solution, and the crystallized material has played the role of a seed for the newly-input material, which is beneficial to the growth and precipitation of the crystals of the newly-input material and ensures the uniformity of the grains. In addition, the multi-stage continuous cooling crystallization method is used for crystallization, so that more materials can be crystallized at one time, and therefore the number of cleanings is greatly reduced, and the equipment utilization rate is high and the production capacity is high. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] In order to more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the specific embodiments or the description of the prior art. Obviously, the drawings described below are some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0032] Figure 1 A schematic diagram of a multi-stage continuous cooling crystallization device for acetaminophen provided in an embodiment of the present invention;

[0033] Figure 2 A schematic diagram of a first crystallization kettle and a heat exchange mechanism provided in an embodiment of the present invention;

[0034] Figure 3 A schematic diagram of a baffle and a first crystallization kettle provided in an embodiment of the present invention;

[0035] Figure 4 A distribution diagram of the baffles provided in the first crystallization kettle according to an embodiment of the present invention;

[0036] Figure 5 This is the particle size distribution diagram of the acetaminophen finished product obtained in Experiment 1;

[0037] Figure 6 This is the liquid chromatogram of the acetaminophen product obtained in Experiment 1;

[0038] Figure 7 This is the particle size distribution diagram of the acetaminophen finished product obtained in Experiment 2;

[0039] Figure 8 This is the liquid chromatogram of the acetaminophen product obtained in Experiment 2.

[0040] Icons: 1. Steam inlet; 2. Steam outlet; 3. Acylation kettle; 4. Acylation pump; 5. Primary condensate inlet; 6. Primary condensate outlet; 7. Screw stirrer; 8. Primary crystallization kettle; 9. Primary reflux detector; 10. Primary heat exchanger; 11. Primary transfer pump; 12. Secondary condensate inlet; 13. Secondary condensate outlet; 14. Secondary crystallization kettle; 15. Secondary reflux detector; 16. Secondary heat exchanger; 17. Secondary transfer pump; 18. Thirdary condensate inlet; 19. Third-stage condensate outlet; 20. Third-stage crystallization kettle; 21. Third-stage transfer pump; 22. Fourth-stage condensate inlet; 23. Fourth-stage condensate outlet; 24. Fourth-stage crystallization kettle; 25. Fourth-stage transfer pump; 26. Fifth-stage condensate inlet; 27. Fifth-stage condensate outlet; 28. Fifth-stage crystallization kettle; 29. ​​Fifth-stage transfer pump; 30. Centrifuge; 31. Baffle; 32. Circulating water heat exchanger; 33. Circulating water insulation kettle; 34. Circulating water pump; 35. Thermometer; 36. Flowmeter. DETAILED DESCRIPTION

[0041] The following will clearly and completely describe the technical solutions of the present invention in conjunction with the embodiments. Obviously, the embodiments described are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0042] Example 1:

[0043] Embodiment 1 of the present invention provides a multi-stage continuous cooling crystallization method for acetaminophen, comprising the following steps:

[0044] S1: Perform at least five stages of continuous cooling crystallization, and inject circulating water of a set temperature into the jacket of the crystallization kettle during each stage of cooling crystallization; wherein:

[0045] During the first few stages of crystallization, the difference between the initial temperature of the material entering the crystallization kettle and the initial temperature of the circulating water is 13°C-25°C;

[0046] During the last crystallization, the initial temperature of the material entering the crystallization kettle is 30°C-35°C, and the difference between the initial temperature of the material entering the crystallization kettle and the initial temperature of the circulating water is 21°C-28°C;

[0047] S2: Open the transfer pumps between the crystallization kettles in sequence according to the set time.

[0048] In this embodiment, during the first few stages of crystallization, the difference between the initial temperature of the material entering the crystallization kettle and the initial temperature of the circulating water entering the crystallization kettle jacket is controlled to 13°C-25°C. During the final crystallization, the initial temperature of the material entering the crystallization kettle is controlled to 30°C-35°C, and the difference between the initial temperature of the material entering the crystallization kettle and the initial temperature of the circulating water is controlled to 21°C-28°C.

[0049] As can be seen, this multi-stage continuous cooling crystallization method uses different water temperatures to gradually cool the material, avoiding the problems of uneven grain size, low grain purity, and poor quality caused by crystal explosions caused by the large temperature difference between the material and the refrigerant and the rapid cooling rate in the early cooling period. Moreover, because the circulating water temperature in each crystallization kettle is constant, there is no need to frequently change water at different temperatures, reducing damage to the crystallization kettle caused by alternating hot and cold cycles.

[0050] Furthermore, it should be noted that the initial temperature of the material within the crystallization kettle of conventional crystallization equipment was generally above 110°C, and the temperature of the circulating water within the crystallization kettle was approximately 15°C-30°C. Therefore, the difference between the initial temperature of the material and the temperature of the circulating water was at least 80°C-95°C. Due to the large temperature difference, the local temperature of the material near the kettle wall dropped sharply, rapidly forming a supersaturated solution and precipitating crystals first. In contrast, the material in the center of the kettle cooled more slowly and reached saturation later. This asynchrony in the crystallization process in space and time resulted in uneven grain growth rates and an overly wide grain size distribution in the final product. Furthermore, the drastic local cooling also easily caused scaling problems on the surface of the kettle wall.

[0051] In contrast, in this embodiment, the difference between the initial temperature of the material entering the crystallization kettle and the initial temperature of the circulating water entering the crystallization kettle jacket is much less than 80°C-95°C. Due to the small temperature difference, the local temperature will not drop suddenly to form a local supersaturated solution, and the material that has been crystallized acts as a seed for the newly entered material, which is beneficial to the growth and precipitation of the crystals of the newly entered material and ensures the uniformity of the grains.

[0052] In addition, a multi-stage continuous cooling crystallization method is used for crystallization, so that more materials can be crystallized at one time. Therefore, the number of cleanings is greatly reduced, and the equipment utilization rate and production capacity are high.

[0053] In some embodiments, step S1 further includes turning on the spiral agitator 7 in each crystallization kettle.

[0054] It should be noted that acetaminophen can be crystallized by a five-stage continuous cooling crystallization method, a six-stage continuous cooling crystallization method or a seven-stage continuous cooling crystallization method.

[0055] The following is an example of a five-stage continuous cooling crystallization method:

[0056] The five-stage continuous cooling crystallization method specifically includes:

[0057] The first step: circulating water at 90°C to 92°C, circulating water at 70°C to 72°C, circulating water at 50°C to 52°C, circulating water at 30°C to 32°C and circulating water at 7°C to 9°C are respectively introduced into the jacket of the first crystallization kettle 8, the jacket of the second crystallization kettle 14, the jacket of the third crystallization kettle 20, the jacket of the fourth crystallization kettle 24 and the jacket of the fifth crystallization kettle 28.

[0058] In the second step, the spiral agitators 7 of the first-stage crystallization kettle 8, the second-stage crystallization kettle 14, the third-stage crystallization kettle 20, the fourth-stage crystallization kettle 24 and the fifth-stage crystallization kettle 28 are turned on.

[0059] The third step: acylation pump 4 is started and continuously operated, and the material in the acylation kettle 3 is transported to the first-level crystallization kettle 8 through the acylation pump 4 for crystallization, wherein, the starting material temperature is 110 ℃ in the first-level crystallization kettle 8, when the material is full of the first-level crystallization kettle 8, open the first-level transfer pump 11 and continuously operate (at this moment, the acylation pump 4 is also in operation), the part of the material in the first-level crystallization kettle 8 is transported to the second-level crystallization kettle 14 through the first-level transfer pump 11, and the material after the primary cooling enters the second-level crystallization kettle 14 and carries out secondary crystallization; when the material is full of the second-level crystallization kettle 14, open the second-level transfer pump 17 and continuously operate (at this moment, the acylation pump 4 and the first-level transfer pump 11 are also in operation), the part of the material in the second-level crystallization kettle 14 is transported to the tertiary crystallization kettle 20 through the second-level transfer pump 17, and the material after the secondary cooling enters the tertiary crystallization kettle 20 and carries out tertiary crystallization; after the material is full of the tertiary crystallization kettle 20, open the tertiary transfer pump 21 and continuously operate (at this moment, the acylation pump 4, the first-level transfer pump 11 and the first-level transfer pump 11 are also in operation), The transfer pump 11 and the secondary transfer pump 17 are also in operation), part of the material in the tertiary crystallization kettle 20 is transported to the fourth crystallization kettle 24 via the third transfer pump 21, and the material after three coolings enters the fourth crystallization kettle 24 for four-stage crystallization; after the material fills the fourth crystallization kettle 24, the fourth transfer pump 25 is turned on and continues to run (at this time, the acylation pump 4, the first transfer pump 11, the second transfer pump 17 and the third transfer pump 21 continue to run), part of the material in the fourth crystallization kettle 24 The material is transported to the fifth-stage crystallization kettle 28 via the fourth-stage transfer pump 25, and the material after the fourth-stage cooling enters the fifth-stage crystallization kettle 28 for fifth-stage crystallization; after the material fills the fifth-stage crystallization kettle 28, the fifth-stage transfer pump 29 is turned on and continuously operated (at this time, the acylation pump 4, the first-stage transfer pump 11, the second-stage transfer pump 17, the third-stage transfer pump 21 and the fourth-stage transfer pump 25 are continuously operated), and the material liquid cooled to the centrifugal temperature is pumped into the centrifuge 30 via the fifth-stage transfer pump 29 for centrifugation to obtain a crude intermediate.

[0060] Afterwards, the acylation pump 4, the first-stage transfer pump 11, the second-stage transfer pump 17, the third-stage transfer pump 21, the fourth-stage transfer pump 25 and the fifth-stage transfer pump 29 continue to operate at the set power to ensure that the material is continuously fed in and out at 7.8 m3 / h.

[0061] It should be noted that during the primary crystallization, the temperature of the starting material in the primary crystallization kettle 8 is 110°C, the inlet temperature (initial temperature) of the circulating water in the jacket of the primary crystallization kettle 8 is 90°C to 92°C, and the outlet temperature of the circulating water in the jacket of the primary crystallization kettle 8 is 95°C to 97°C.

[0062] During secondary crystallization, the starting material temperature in the secondary crystallization kettle 14 is 95°C, the inlet temperature of the circulating water in the jacket of the secondary crystallization kettle 14 is 70°C to 72°C, and the outlet temperature of the circulating water in the jacket of the secondary crystallization kettle 14 is 75°C to 77°C.

[0063] During the tertiary crystallization, the starting material temperature in the tertiary crystallization kettle 20 is 75°C, the inlet temperature of the circulating water in the jacket of the tertiary crystallization kettle 20 is 50°C to 52°C, and the outlet temperature of the circulating water in the jacket of the tertiary crystallization kettle 20 is 55°C to 57°C.

[0064] During the fourth stage crystallization, the starting material temperature in the fourth stage crystallization kettle 24 is 55°C, the inlet temperature of the circulating water in the jacket of the fourth stage crystallization kettle 24 is 30°C to 32°C, and the outlet temperature of the circulating water in the jacket of the fourth stage crystallization kettle 24 is 35°C to 37°C.

[0065] During the five-stage crystallization, the starting material temperature in the five-stage crystallization kettle 28 is 35°C, the inlet temperature of the circulating water in the jacket of the five-stage crystallization kettle 28 is 7°C to 9°C, the outlet temperature of the circulating water in the jacket of the five-stage crystallization kettle 28 is 12°C to 14°C, and the final centrifugal temperature of the feed liquid is 15°C to 18°C ​​and enters the centrifuge 30 for centrifugation.

[0066] It should be understood that during the first crystallization, the difference between the temperature of the starting material in the first crystallization kettle 8 and the inlet temperature of the circulating water in the jacket of the first crystallization kettle 8 is 18°C-20°C. During the second crystallization, the difference between the temperature of the starting material in the second crystallization kettle 14 and the inlet temperature of the circulating water in the jacket of the second crystallization kettle 14 is 23°C-25°C. During the third crystallization, the difference between the temperature of the starting material in the third crystallization kettle 20 and the inlet temperature of the circulating water in the jacket of the third crystallization kettle 20 is 23°C-25°C. During the fourth crystallization, the difference between the temperature of the starting material in the fourth crystallization kettle 24 and the inlet temperature of the circulating water in the jacket of the fourth crystallization kettle 24 is 23°C-25°C. During the fifth crystallization, the difference between the temperature of the starting material in the fifth crystallization kettle 28 and the inlet temperature of the circulating water in the jacket of the fifth crystallization kettle 28 is 26°C-28°C.

[0067] It can be seen that the five-stage continuous cooling crystallization method is used for crystallization in this embodiment. Five crystallization kettles are used to perform gradient cooling of the material using different water temperatures. This avoids the problems of uneven grain size, low grain purity, and poor quality caused by the crystal burst caused by the large temperature difference between the material and the refrigerant and the fast cooling rate in the early stage of cooling. Moreover, since the circulating water temperature of the crystallization kettle at each level is constant, there is no need to frequently change the water at different temperatures, which reduces the damage to the crystallization kettle caused by alternating hot and cold. For the product, the temperature difference is small, which is more conducive to the nucleation and growth of crystals.

[0068] In addition, since the temperature difference between the material and the circulating water is small during each stage of crystallization, the crystal size is uniform and the crystal shape is good under steady-state operation.

[0069] In order to prove that the crystal size of acetaminophen finished product produced by the five-stage continuous cooling crystallization method is uniform and the crystal form is good, the following two groups of comparative experiments were conducted:

[0070] Experiment 1:

[0071] 1920 kg of acetaminophen, 2000 kg of glacial acetic acid, and 4000 L of mother liquor were dissolved and heated to 71°C. The steam was then turned off to stop the heating, and the solution was then pressed into acylation kettle 3. The solution was acylated in acylation kettle 3 and heated to reflux (108.3°C) for 5 hours. Acid was then collected at 1 / 3 and 1 / 2 for 1 hour each. Full acid collection was then performed, with a total acid collection volume of 3400 kg and an end point temperature of 110°C, before discharging.

[0072] Then, circulating water at 90°C to 92°C, circulating water at 70°C to 72°C, circulating water at 50°C to 52°C, circulating water at 30°C to 32°C and circulating water at 7°C to 9°C were introduced into the jacket of the first crystallization kettle 8, the jacket of the second crystallization kettle 14, the jacket of the third crystallization kettle 20, the jacket of the fourth crystallization kettle 24 and the jacket of the fifth crystallization kettle 28 respectively; and the spiral agitator 7 of the first crystallization kettle 8, the second crystallization kettle 14, the third crystallization kettle 20, the fourth crystallization kettle 24 and the fifth crystallization kettle 28 were opened respectively.

[0073] The acylation pump 4 is started and continuously operated, and part of the material in the acylation kettle 3 is transported to the first-level crystallization kettle 8 through the acylation pump 4 for crystallization. After that, the first-level transfer pump 11 is started and continuously operated, and part of the material in the first-level crystallization kettle 8 is transported to the second-level crystallization kettle 14 through the first-level transfer pump 11. The material after the first cooling (95°C) enters the second-level crystallization kettle 14 for secondary crystallization; after that, the second-level transfer pump 17 is started and continuously operated, and part of the material in the second-level crystallization kettle 14 is transported to the third-level crystallization kettle 20 through the second-level transfer pump 17. The material after the second cooling (75°C) enters the third-level crystallization kettle 20 for tertiary crystallization; after that, the third-level transfer pump is started 21 and continues to operate, part of the material in the third crystallization kettle 20 is transported to the fourth crystallization kettle 24 via the third transfer pump 21, and the material (55°C) after three coolings enters the fourth crystallization kettle 24 for fourth-stage crystallization; subsequently, the fourth transfer pump 25 is started and continuously operated, and part of the material in the fourth crystallization kettle 24 is transported to the fifth crystallization kettle 28 via the fourth transfer pump 25, and the material (35°C) after four coolings enters the fifth crystallization kettle 28 for fifth-stage crystallization; finally, the fifth transfer pump 29 is started and continuously operated, and the feed liquid that has been reduced to the centrifugal temperature (16°C) is pumped into the centrifuge 30 via the fifth transfer pump 29 for centrifugation to obtain a crude intermediate. Then, the acylation pump 4, the first-stage transfer pump 11, the second-stage transfer pump 17, the third-stage transfer pump 21, the fourth-stage transfer pump 25 and the fifth-stage transfer pump 29 continue to operate at the set power, so that the material is continuously fed and discharged at 7.8 m3 / h to continuously obtain crude acetaminophen.

[0074] Finally, the obtained crude acetaminophen product is decolorized by adding purified water and activated carbon and heating to 103°C, and keeping it at this temperature for 30 minutes, followed by filter pressing, and then refined by centrifugation to obtain a wet product, which is then dried and packaged to obtain the finished acetaminophen product.

[0075] Experiment 2: 1920 kg of acetaminophen, 2000 kg of glacial acetic acid, and 4000 L of mother liquor were dissolved and heated to 71°C. The steam was then turned off to stop heating, and the dissolved material was then pressed into the acylation kettle 3.

[0076] The solution was acylated in the acylation kettle 3 and heated to reflux (108.3°C) for 5 hours. A 1 / 3 acid extraction and a 1 / 2 acid extraction were then performed for 1 hour each. Full acid extraction was then performed, with a total acid extraction volume of 3400 kg. When the terminal temperature reached 110°C, 30°C circulating water was introduced into the jacket of the acylation kettle 3. The spiral stirrer 7 in the acylation kettle 3 was turned on. After a period of reaction, the solution in the acylation kettle 3 was centrifuged to obtain crude acetaminophen.

[0077] Finally, the crude acetaminophen product is decolorized by adding purified water and activated carbon and heating to 103°C, and keeping at this temperature for 30 minutes, followed by filter pressing, and then refined, crystallized and centrifuged to obtain a wet product, which is then dried and packaged to obtain the finished acetaminophen product.

[0078] Figure 5 This is the particle size distribution diagram of the acetaminophen finished product obtained in Experiment 1. Figure 6 This is the liquid chromatogram of the acetaminophen product obtained in Experiment 1. Figure 7 This is the particle size distribution diagram of the acetaminophen finished product obtained in Experiment 2. Figure 8 This is the liquid chromatogram of the acetaminophen product obtained in Experiment 2.

[0079] from Figure 5 and Figure 7 It is not difficult to find that the particle size crystal distribution of the acetaminophen finished product obtained in Experiment 1 is uniform and the crystal form is good. The particle size crystal distribution of the acetaminophen finished product obtained in Experiment 2 is dispersed. Figure 6 It can be seen that the purity of the acetaminophen finished product obtained in Experiment 1 is 99.69%, and the purity of the acetaminophen finished product obtained in Experiment 2 is 98.97%. The purity of the acetaminophen finished product obtained in Experiment 1 is also higher.

[0080] In some embodiments, a six-stage continuous cooling crystallization method is used for crystallization, specifically:

[0081] During the primary crystallization, the initial temperature of the material is 110°C, the initial temperature of the circulating water is 90°C to 92°C, and the difference between the initial temperature of the material and the initial temperature of the circulating water is 18°C ​​to 20°C.

[0082] During secondary crystallization, the initial temperature of the material is 95°C, the initial temperature of the circulating water is 73°C to 75°C, and the difference between the initial temperature of the material and the initial temperature of the circulating water is 20°C to 22°C.

[0083] During the tertiary crystallization, the initial temperature of the material is 75°C, the initial temperature of the circulating water is 58°C to 60°C, and the difference between the initial temperature of the material and the initial temperature of the circulating water is 15°C to 17°C.

[0084] During the fourth stage crystallization, the initial temperature of the material is 60°C, the initial temperature of the circulating water is 43°C to 45°C, and the difference between the initial temperature of the material and the initial temperature of the circulating water is 15°C to 17°C.

[0085] During the fifth stage crystallization, the initial temperature of the material is 45°C, the initial temperature of the circulating water is 28°C to 30°C, and the difference between the initial temperature of the material and the initial temperature of the circulating water is 15°C to 17°C.

[0086] During the sixth stage crystallization, the initial temperature of the material is 30°C, the initial temperature of the circulating water is 7°C to 9°C, and the difference between the initial temperature of the material and the initial temperature of the circulating water is 21°C to 23°C.

[0087] In some embodiments, a seven-stage continuous cooling crystallization method is used for crystallization, specifically:

[0088] During the primary crystallization, the initial temperature of the material is 110°C, the initial temperature of the circulating water is 90°C to 92°C, and the difference between the initial temperature of the material and the initial temperature of the circulating water is 18°C ​​to 20°C.

[0089] During secondary crystallization, the initial temperature of the material is 95°C, the initial temperature of the circulating water is 80°C to 82°C, and the difference between the initial temperature of the material and the initial temperature of the circulating water is 13°C to 15°C.

[0090] During the tertiary crystallization, the initial temperature of the material is 82°C, the initial temperature of the circulating water is 67°C to 69°C, and the difference between the initial temperature of the material and the initial temperature of the circulating water is 13°C to 15°C.

[0091] During the fourth stage crystallization, the initial temperature of the material is 69°C, the initial temperature of the circulating water is 54°C to 56°C, and the difference between the initial temperature of the material and the initial temperature of the circulating water is 13°C to 15°C.

[0092] During the fifth stage crystallization, the initial temperature of the material is 56°C, the initial temperature of the circulating water is 41°C to 43°C, and the difference between the initial temperature of the material and the initial temperature of the circulating water is 13°C to 15°C.

[0093] During the sixth stage crystallization, the initial temperature of the material is 43°C, the initial temperature of the circulating water is 28°C to 30°C, and the difference between the initial temperature of the material and the initial temperature of the circulating water is 13°C to 15°C.

[0094] During the seventh stage crystallization, the initial temperature of the material is 30°C, the initial temperature of the circulating water is 7°C to 9°C, and the difference between the initial temperature of the material and the initial temperature of the circulating water is 21°C to 23°C.

[0095] Example 2:

[0096] A second embodiment of the present invention provides a multi-stage continuous cooling crystallization device for acetaminophen, which is used to implement the multi-stage continuous cooling crystallization method of the first embodiment. The multi-stage continuous cooling crystallization device for acetaminophen includes a plurality of crystallization kettles and a heat exchange mechanism corresponding to each crystallization kettle; a material conveying mechanism for conveying material is installed between any two adjacent crystallization kettles; the crystallization kettle includes a kettle body and a jacket provided on the outside of the kettle body, and the jacket is provided with a condensed water inlet and a condensed water outlet;

[0097] Each crystallization kettle is equipped with a corresponding heat exchange mechanism, which is used to exchange heat with the material in the corresponding crystallization kettle to reduce the temperature of the material; the heat exchange mechanism includes a circulating water pump 34 and a circulating water insulation kettle 33, the water inlet of the circulating water pump 34 is connected to the water outlet of the circulating water insulation kettle 33, the water outlet of the circulating water pump 34 is connected to the condensed water inlet on the jacket, and the circulating water insulation kettle 33 is connected to the condensed water outlet on the jacket through a pipeline; the circulating water pump 34 is used to extract the circulating water in the circulating water insulation kettle 33 and inject it into the jacket of the crystallization kettle.

[0098] As a specific embodiment, Figure 1 As shown, there are five crystallization kettles, which include a first-stage crystallization kettle 8, a second-stage crystallization kettle 14, a third-stage crystallization kettle 20, a fourth-stage crystallization kettle 24, and a fifth-stage crystallization kettle 28. The multi-stage continuous cooling crystallization device for acetaminophen also includes an acylation pump 4 and a centrifuge 30. The feed port of the acylation pump 4 is connected to the discharge port of the acylation kettle 3 through a pipeline, and the discharge port of the acylation pump 4 is connected to the feed port of the first-stage crystallization kettle 8 through a pipeline.

[0099] The material conveying mechanism includes transfer pumps and pipelines. Specifically, for the convenience of description, the transfer pumps in the five material conveying mechanisms are named as the first-stage transfer pump 11, the second-stage transfer pump 17, the third-stage transfer pump 21, the fourth-stage transfer pump 25, and the fifth-stage transfer pump 29.

[0100] Among them, the feed port of the first-stage transfer pump 11 is connected to the discharge port of the first-stage crystallization kettle 8 through a pipeline, and the discharge port of the first-stage transfer pump 11 is connected to the feed port of the second-stage crystallization kettle 14 through a pipeline; the feed port of the second-stage transfer pump 17 is connected to the discharge port of the second-stage crystallization kettle 14 through a pipeline, and the discharge port of the second-stage transfer pump 17 is connected to the feed port of the tertiary crystallization kettle 20 through a pipeline; the feed port of the tertiary transfer pump 21 and the discharge port of the tertiary crystallization kettle 20 are connected by a pipeline, and the tertiary crystallization kettle 20 is connected to the feed port of the tertiary transfer pump 21 through a pipeline. The discharge port of the transfer pump 21 is connected to the feed port of the fourth-stage crystallization kettle 24 by a pipeline; the feed port of the fourth-stage transfer pump 25 is connected to the discharge port of the fourth-stage crystallization kettle 24 by a pipeline, and the discharge port of the fourth-stage transfer pump 25 is connected to the feed port of the fifth-stage crystallization kettle 28 by a pipeline; the feed port of the fifth-stage transfer pump 29 is connected to the discharge port of the fifth-stage crystallization kettle 28 by a pipeline, and the discharge port of the fifth-stage transfer pump 29 is connected to the feed port of the centrifuge 30 by a pipeline.

[0101] In this embodiment, the first-stage crystallization kettle 8, the second-stage crystallization kettle 14, the third-stage crystallization kettle 20, the fourth-stage crystallization kettle 24 and the fifth-stage crystallization kettle 28 are all jacketed. Figure 1 As shown, the jacket of the first-stage crystallization kettle 8 is provided with a first-stage condensed water inlet 5 and a first-stage condensed water outlet 6, and the first-stage condensed water inlet 5 is lower than the first-stage condensed water outlet 6. The jacket of the second-stage crystallization kettle 14 is provided with a second-stage condensed water inlet 12 and a second-stage condensed water outlet 13, and the second-stage condensed water inlet 12 is lower than the second-stage condensed water outlet 13. The jacket of the third-stage crystallization kettle 20 is provided with a third-stage condensed water inlet 18 and a third-stage condensed water outlet 19, and the third-stage condensed water inlet 18 is lower than the third-stage condensed water outlet 19. The jacket of the fourth-stage crystallization kettle 24 is provided with a fourth-stage condensed water inlet 22 and a fourth-stage condensed water outlet 23, and the fourth-stage condensed water inlet 22 is lower than the fourth-stage condensed water outlet 23. The jacket of the fifth-stage crystallization kettle 28 is provided with a fifth-stage condensed water inlet 26 and a fifth-stage condensed water outlet 27, and the fifth-stage condensed water inlet 26 is lower than the fifth-stage condensed water outlet 27.

[0102] In this embodiment, a five-stage cooling system is adopted to cool the temperature in stages. Different water temperatures are used in the five-stage crystallization kettle to perform gradient cooling on the material. The starting material temperature in the first-stage crystallization kettle 8 is 110°C, and the initial temperature of the jacket circulating water is set to 90-92°C. The starting material temperature in the second-stage crystallization kettle 14 is 95°C, and the initial temperature of the jacket circulating water is set to 70-72°C. The starting material temperature in the third-stage crystallization kettle 20 is 75°C, and the initial temperature of the jacket circulating water is set to 50-52°C. The starting material temperature in the fourth-stage crystallization kettle 24 is 55°C, and the initial temperature of the jacket circulating water is set to 30-32°C. The starting material temperature in the fifth-stage crystallization kettle 28 is 35°C, and the initial temperature of the jacket circulating water is set to 7-9°C.

[0103] It can be seen that this embodiment uses five crystallization kettles with different water temperatures to perform gradient cooling on the material, avoiding the problems of uneven grain size, low grain purity and poor quality caused by crystal explosion due to the large temperature difference between the material and the refrigerant and the fast cooling rate in the early stage of cooling, and reducing the probability of scaling of the crystallization kettle.

[0104] Moreover, since the circulating water temperature of each stage of the crystallization kettle is constant, there is no need to frequently replace water of different temperatures, which reduces the damage to the crystallization kettle caused by alternating hot and cold. For the product, the temperature difference of each crystallization is small, which is more conducive to the nucleation and growth of crystals, and the crystal particle size is uniform and the crystal shape is good.

[0105] Furthermore, it's important to note that conventional crystallization equipment, consisting of an acylation kettle and a crystallization kettle, requires flushing with dilute acetic acid and deionized water, respectively, after each crystallization reaction to remove residual material and mother liquor. Consequently, at least five hours of this flushing process are required out of a 12-hour operating period, resulting in limited operating time and low production capacity.

[0106] In contrast, in this embodiment, since five crystallization kettles are used to adopt a five-stage continuous cooling crystallization method for crystallization, more materials can be crystallized at one time. Therefore, the number of cleanings is greatly reduced, raw materials are continuously fed in, and products are continuously discharged. There is no need to frequently start and stop the equipment, and only regular cleaning is required. The equipment utilization rate is high and the production capacity is high.

[0107] In some embodiments, as Figure 2 As shown, the heat exchange mechanism further includes a circulating water heat exchanger 32, the water inlet of the circulating water heat exchanger 32 being connected to the condensed water outlet on the crystallization kettle, the water outlet of the circulating water heat exchanger 32 being connected to the first water inlet of the circulating water insulation kettle 33, and the second water inlet of the circulating water insulation kettle 33 being used to supply circulating water. For example, an electric hot water tank heats water to a set temperature, and then the hot water in the electric hot water tank is pumped into the circulating water insulation kettle 33 through a water pump and a pipeline. Then, the circulating water pump 34 pumps the circulating water in the circulating water insulation kettle 33 into the jacket of the crystallization kettle.

[0108] It should be noted that the function of the circulating water heat exchanger 32 is to reduce the temperature of the circulating water flowing out of the condensed water outlet of the crystallization kettle so as to facilitate its recycling.

[0109] Specifically, such as Figure 2As shown, taking the primary crystallization kettle 8 as an example, the temperature of the starting material in the primary crystallization kettle 8 is 110°C, the initial temperature of the jacket circulating water is 90-92°C, and the circulating water pump 34 pumps water with an initial temperature of 90-92°C into the jacket of the primary crystallization kettle 8. The temperature of the circulating water discharged from the condensate outlet of the jacket of the primary crystallization kettle 8 rises to 95-97°C, and then after cooling by the circulating water heat exchanger 32, the circulating water temperature is reduced to 90-92°C and refluxes to the circulating water insulation kettle 33 for recycling, ensuring that the initial temperature of the circulating water pumped into the jacket of the primary crystallization kettle 8 can always be maintained at 90-92°C.

[0110] In some embodiments, as Figure 2 As shown, a thermometer 35 and a flow meter 36 are installed on the pipeline between the circulating water pump 34 and the condensed water inlet of the crystallizer. They are used to detect the initial temperature and initial flow of the circulating water injected into the crystallizer jacket.

[0111] It should be noted that this embodiment only shows a schematic diagram of the heat exchange mechanism connected to the first-level crystallization kettle 8. Since the heat exchange mechanisms on the second-level crystallization kettle 14, the third-level crystallization kettle 20, the fourth-level crystallization kettle 24 and the fifth-level crystallization kettle 28 are the same as the structure of the heat exchange mechanism on the first-level crystallization kettle 8, the heat exchange mechanisms on the second-level crystallization kettle 14, the third-level crystallization kettle 20, the fourth-level crystallization kettle 24 and the fifth crystallization kettle 28 are not shown in the present invention. For details, please refer to the structure of the heat exchange mechanism connected to the first-level crystallization kettle 8.

[0112] It should be understood that in the past, during the crystallization process in the crystallization kettle, due to the high temperature of the material, some solvents or reactants may evaporate, forming steam escape, usually a mixed steam of glacial acetic acid and water. Glacial acetic acid itself has high volatility, especially in a high temperature environment, its molecules are more likely to change from liquid to gas.

[0113] In previous crystallization kettles, due to the large temperature difference between the material and the refrigerant in the early stage of cooling, the cooling rate is too fast, which may cause a sudden drop in local temperature and form supersaturated steam, thereby exacerbating steam overflow. The formation of supersaturated steam will increase the amount of steam escape, especially near the exhaust port of the crystallization kettle, which will cause the solid-liquid balance in the crystallization kettle to be broken.

[0114] Different from this, in this embodiment, Figure 1 As shown, the acetaminophen multi-stage continuous cooling crystallization device further includes a primary reflux detector 9, a primary heat exchanger 10, a secondary heat exchanger 16 and a secondary reflux detector 15.

[0115] Furthermore, the exhaust port of the first crystallization kettle 8 and the air inlet of the first heat exchanger 10 are connected by a pipe, and the first reflux detector 9 is installed on the pipe between the first crystallization kettle 8 and the first heat exchanger 10; the exhaust port of the second crystallization kettle 14 and the second heat exchanger 16 are connected by a pipe, and the second reflux detector 15 is installed on the pipe between the second crystallization kettle 14 and the second heat exchanger 16.

[0116] It should be understood that, due to the higher initial temperatures of the materials entering the primary crystallization kettle 8 and the secondary crystallization kettle 14, the materials entering the primary crystallization kettle 8 and the secondary crystallization kettle 14 are more likely to exacerbate the overflow of mixed steam than the materials entering the remaining three crystallization kettles. Therefore, in this application, reflux detectors and heat exchangers are only installed on the primary crystallization kettle 8 and the secondary crystallization kettle 14. Refusal detectors and heat exchangers are not installed on the tertiary crystallization kettle 20, the fourth crystallization kettle 24, and the fifth crystallization kettle 28.

[0117] The following is an explanation using the first-stage crystallization kettle 8 as an example: the exhaust port of the first-stage crystallization kettle 8 is connected to the first-stage heat exchanger 10 via a pipe. When the temperature inside the first-stage crystallization kettle 8 rises, a mixed vapor of glacial acetic acid and water is generated and escapes upward. These vapors will enter the first-stage heat exchanger 10 through the pipe. A cooling medium (such as cooling water) flows inside the first-stage heat exchanger 10. After the mixed vapor enters the first-stage heat exchanger 10, it exchanges heat with the cooling medium, the temperature drops rapidly, and the vapor condenses into liquid. The condensed liquid is sent back to the first-stage crystallization kettle 8 through the pipe. In this way, the overflow of the vapor is reduced and the condensed liquid is reintroduced into the crystallization system, maintaining the solid-liquid equilibrium.

[0118] The primary reflux detector 9 is installed on the pipeline and can monitor the flow rate and temperature of the reflux liquid in real time. By detecting these parameters of the reflux liquid, the generation of steam in the primary crystallization kettle 8 and the condensation effect of the primary heat exchanger 10 can be indirectly understood.

[0119] The primary reflux detector 9 feeds the monitored data back to the control system, which automatically adjusts the flow rate or temperature of the cooling medium in the primary heat exchanger 10 based on this data to control the condensation efficiency. For example, if the flow rate of the reflux liquid decreases, it indicates that the condensation effect of the primary heat exchanger 10 may be insufficient. The control system will increase the flow rate of the cooling medium or lower its temperature to improve the condensation efficiency, so that more steam condenses into liquid and flows back to the primary crystallizer 8.

[0120] In this way, through the monitoring and feedback control of the first-level reflux detector 9, it is ensured that the condensed liquid can be returned to the first-level crystallization kettle 8 in a timely and appropriate manner to replenish the amount of liquid reduced due to steam overflow, thereby maintaining the solid-liquid balance in the crystallization kettle, preventing the evaporation of high-temperature solvent from affecting the material concentration and causing the risk of crystal explosion, and ensuring the stable progress of the crystallization process.

[0121] As for the working process of the secondary reflux detector 15 and the secondary heat exchanger 16 on the secondary crystallization kettle 14, refer to the above-mentioned primary reflux detector 9 and primary heat exchanger 10, so they are not repeated here.

[0122] Furthermore, it should be noted that the initial temperature of the material within the crystallization kettle of conventional crystallization equipment was approximately 110°C, and the temperature of the circulating water within the crystallization kettle was approximately 15°C-30°C. Therefore, the difference between the initial material temperature and the circulating water temperature was approximately 80°C-95°C. Due to this large temperature difference, the local temperature of the material near the kettle wall dropped sharply, rapidly forming a supersaturated solution and precipitating crystals first. In contrast, the material in the center of the kettle cooled more slowly and reached saturation much later. This asynchrony in the crystallization process in space and time resulted in uneven grain growth rates and an overly wide grain size distribution in the final product. Furthermore, the drastic local cooling also easily caused scaling on the kettle wall surface.

[0123] In the present application, the initial temperature of the material entering the primary crystallization kettle 8 is approximately 110° C., and the temperature of the circulating water entering the jacket of the primary crystallization kettle 8 is 90-92° C. That is, the difference between the initial temperature of the material entering the primary crystallization kettle 8 and the temperature of the circulating water entering the jacket of the primary crystallization kettle 8 is 18° C.-20° C., which is much smaller than 80° C.-95° C.

[0124] The initial temperature of the material entering the secondary crystallization kettle 14 is 95° C., and the temperature of the circulating water entering the jacket of the secondary crystallization kettle 14 is 70-72° C. That is, the difference between the initial temperature of the material entering the secondary crystallization kettle 14 and the temperature of the circulating water entering the jacket of the secondary crystallization kettle 14 is 23-25° C., which is much smaller than 80-95° C.

[0125] It can be seen that in this embodiment, since the difference between the initial temperature of the material entering the crystallization kettle and the water temperature of the circulating water entering the crystallization kettle jacket is small, it will not cause a sudden drop in local temperature to form a local supersaturated solution, and the crystallized material has played a role as a seed for the newly entered material, which is beneficial to the growth and precipitation of the crystals of the newly entered material, thereby ensuring the uniformity of the grains.

[0126] In some embodiments, a stirring device is installed in each of the first-stage crystallization kettle 8, the second-stage crystallization kettle 14, the third-stage crystallization kettle 20, the fourth-stage crystallization kettle 24, and the fifth-stage crystallization kettle 28. The stirring device is a spiral blade stirrer. Conventional crystallization equipment uses anchor-type stirring, which has high stirring intensity and high shear force, and is prone to secondary nucleation, causing crystal damage and uneven particle size. In contrast, the present embodiment uses a spiral blade stirrer, which has low stirring intensity, minimizes damage to the crystal grains, and ensures uniform grain size.

[0127] In some embodiments, as Figure 3As shown, baffles 31 are installed in each of the first-stage crystallization kettle 8, the second-stage crystallization kettle 14, the third-stage crystallization kettle 20, the fourth-stage crystallization kettle 24, and the fifth-stage crystallization kettle 28. Three baffles 31 are provided. These three baffles 31 are evenly arranged on the inner wall of the crystallization kettle around the axis of the crystallization kettle, and all three baffles 31 are arranged vertically. The purpose of providing baffles 31 is to enhance turbulent mixing, making the crystal growth environment uniform, and also to regulate the crystal suspension state and inhibit sedimentation.

[0128] Specifically, such as Figure 3 and Figure 4 As shown, the volume of the crystallization kettle is 6300 L, the straight section of the kettle is 2200 mm high and 1800 mm in diameter, and the baffles 31 are evenly distributed on the inner wall of the crystallization kettle, with a height of 1600 mm.

[0129] Optionally, the baffle 31 is spiral-shaped, and the baffle 31 is spirally distributed along the inner wall of the crystallization kettle.

[0130] In some embodiments, a control system is included, and the entire acetaminophen multi-stage continuous cooling crystallization device is controlled by the control system. The acylation pump 4, the first-stage reflux detector 9, the first-stage heat exchanger 10, the first-stage transfer pump 11, the second-stage reflux detector 15, the second-stage heat exchanger 16, the second-stage transfer pump 17, the third-stage transfer pump 21, the fourth-stage transfer pump 25, the fifth-stage transfer pump 29, the five spiral agitators 7, the circulating water pump 34, the flow meter 36, etc. in the acetaminophen multi-stage continuous cooling crystallization device are all connected to the control system signal.

[0131] In this embodiment, solenoid valves are installed on the delivery pipelines of the first-stage crystallization kettle 8, the second-stage crystallization kettle 14, the third-stage crystallization kettle 20, the fourth-stage crystallization kettle 24 and the fifth-stage crystallization kettle 28 to control the on-off of the pipelines, and the solenoid valves are connected to the control system signals.

[0132] When using the present acetaminophen multi-stage continuous cooling crystallization device for crystallization, first, the circulating water pumps 34 on the five heat exchange mechanisms are turned on to pump circulating water at 90°C to 92°C, circulating water at 70°C to 72°C, circulating water at 50°C to 52°C, circulating water at 30°C to 32°C and circulating water at 7°C to 9°C into the jacket of the first crystallization kettle 8, the jacket of the second crystallization kettle 14, the jacket of the third crystallization kettle 20, the jacket of the fourth crystallization kettle 24 and the jacket of the fifth crystallization kettle 28, respectively.

[0133] Then, the spiral agitator 7 of the first-stage crystallization kettle 8, the second-stage crystallization kettle 14, the third-stage crystallization kettle 20, the fourth-stage crystallization kettle 24 and the fifth-stage crystallization kettle 28 is turned on. Next, the acylation pump 4 is turned on, and the material in the acylation kettle 3 (initial temperature is 110° C.) is transported to the first-stage crystallization kettle 8 via the acylation pump 4 for crystallization. After the set time, the first-stage transfer pump 11 is turned on, and the material in the first-stage crystallization kettle 8 is transported to the second-stage crystallization kettle 14 via the first-stage transfer pump 11. After the material is cooled once, it enters the second-stage crystallization kettle 14 for secondary crystallization. After the set time, the second-stage transfer pump 17 is turned on, and the material in the second-stage crystallization kettle 14 is transported to the third-stage crystallization kettle 20 via the second-stage transfer pump 17. After the material is cooled twice, it enters the third-stage crystallization kettle 20 for tertiary crystallization. After the set time, After a set time, the three-stage transfer pump 21 is turned on, and the material in the three-stage crystallization kettle 20 is transported to the four-stage crystallization kettle 24 via the three-stage transfer pump 21, and the material after three coolings enters the four-stage crystallization kettle 24 for four-stage crystallization; after a set time, the four-stage transfer pump 25 is turned on, and the material in the four-stage crystallization kettle 24 is transported to the five-stage crystallization kettle 28 via the four-stage transfer pump 25, and the material after four coolings enters the five-stage crystallization kettle 28 for five-stage crystallization; after a set time, the five-stage transfer pump 29 is turned on, and the feed liquid that has been cooled to the centrifugal temperature is pumped into the centrifuge 30 via the five-stage transfer pump 29 for centrifugation to obtain crude acetaminophen.

[0134] Finally, the obtained crude acetaminophen product is decolorized by adding purified water and activated carbon and heating to 103°C, and keeping it at this temperature for 30 minutes, followed by filter pressing, and then refined by centrifugation to obtain a wet product, which is then dried and packaged to obtain the finished acetaminophen product.

[0135] It should be noted that the acylation kettle 3 does not belong to the crystallization equipment. The jacket of the acylation kettle 3 is provided with a steam inlet 1 and a steam outlet 2, and steam is used to maintain a high temperature environment.

[0136] In some embodiments, six crystallization kettles are provided, and the six crystallization kettles are connected by the above-mentioned conveying mechanism, and each crystallization kettle is correspondingly connected to a heat exchange mechanism.

[0137] In some embodiments, seven crystallization kettles are provided, and the seven crystallization kettles are connected by the above-mentioned conveying mechanism, and each crystallization kettle is correspondingly connected to a heat exchange mechanism.

[0138] In the description of the present invention, it should be noted that the terms "upper" and "lower" and other terms indicating orientations or positional relationships are based on the orientations or positional relationships shown in the accompanying drawings and are intended solely to facilitate and simplify the description of the present invention. They are not intended to indicate or imply that the devices or components referred to must have, be constructed, or operate in a specific orientation, and therefore should not be construed as limitations on the present invention. Furthermore, the terms "first" and "second" are used for descriptive purposes only and should not be construed as indicating or implying relative importance.

[0139] In the description of the present invention, it should be noted that, unless otherwise specified or limited, the terms "mounted," "connected," and "connected" should be understood broadly. For example, they can refer to fixed, detachable, or integral connections; mechanical or electrical connections; direct or indirect communication through an intermediary, or internal communication between two components. Furthermore, in the description of the present invention, unless otherwise specified, "plurality" means two or more.

[0140] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A multi-stage continuous cooling crystallization method for acetaminophen, characterized in that: The steps include: S1: Perform at least five stages of continuous cooling crystallization, and inject circulating water of a set temperature into the jacket of the crystallization kettle during each stage of cooling crystallization; wherein: During the first few stages of crystallization, the difference between the initial temperature of the material entering the crystallization kettle and the initial temperature of the circulating water is 13°C-25°C; During the last crystallization, the initial temperature of the material entering the crystallization kettle is 30°C-35°C, and the difference between the initial temperature of the material entering the crystallization kettle and the initial temperature of the circulating water is 21°C-28°C; S2: Open the transfer pumps between the crystallization kettles in sequence according to the set time.

2. A multi-stage continuous cooling crystallization method for acetaminophen according to claim 1, characterized in that, Step S1 also includes: turning on the spiral stirrer (7) in each crystallization kettle.

3. A multi-stage continuous cooling crystallization method for acetaminophen according to claim 1, characterized in that, In step S1, five-stage continuous cooling crystallization is adopted, which specifically includes: During the first stage crystallization, the initial temperature of the material entering the first stage crystallization kettle (8) is 110° C., and the initial temperature of the circulating water in the jacket of the first stage crystallization kettle (8) is 90° C.-92° C.; During the second stage crystallization, the initial temperature of the material entering the secondary crystallization kettle (14) is 95°C, and the initial temperature of the circulating water in the jacket of the secondary crystallization kettle (14) is 70°C-72°C; During the third stage crystallization, the initial temperature of the material entering the third stage crystallization kettle (20) is 75°C, and the initial temperature of the circulating water in the jacket of the third stage crystallization kettle (20) is 50°C-52°C; When the fourth stage crystallization is carried out, the initial temperature of the material entering the fourth stage crystallization kettle (24) is 55°C, and the initial temperature of the circulating water in the jacket of the fourth stage crystallization kettle (24) is 30°C-32°C; When the fifth stage crystallization is carried out, the initial temperature of the material entering the fifth stage crystallization kettle (28) is 35°C, and the initial temperature of the circulating water in the jacket of the fifth stage crystallization kettle (28) is 7°C-9°C.

4. A multi-stage continuous cooling crystallization device for acetaminophen, used for implementing the multi-stage continuous cooling crystallization method according to any one of claims 1 to 3, characterized in that: The acetaminophen multi-stage continuous cooling crystallization device includes a plurality of crystallization kettles and a heat exchange mechanism corresponding to each crystallization kettle; a material conveying mechanism for conveying materials is installed between any two adjacent crystallization kettles; the crystallization kettle includes a kettle body and a jacket provided on the outside of the kettle body, and the jacket is provided with a condensed water inlet and a condensed water outlet; Each crystallization kettle is equipped with a corresponding heat exchange mechanism, and the heat exchange mechanism is used to exchange heat with the material in the corresponding crystallization kettle to reduce the temperature of the material; the heat exchange mechanism includes a circulating water pump (34) and a circulating water insulation kettle (33), the water inlet of the circulating water pump (34) is connected to the water outlet of the circulating water insulation kettle (33), the water outlet of the circulating water pump (34) is connected to the condensed water inlet on the jacket, and the circulating water insulation kettle (33) is connected to the condensed water outlet on the jacket through a pipeline; the circulating water pump (34) is used to extract the circulating water in the circulating water insulation kettle (33) and inject it into the jacket of the crystallization kettle.

5. A multi-stage continuous cooling crystallization device for acetaminophen according to claim 1, characterized in that: The heat exchange mechanism includes a circulating water heat exchanger (32), the water inlet of the circulating water heat exchanger (32) is connected to the condensed water outlet on the crystallization kettle, and the water outlet of the circulating water heat exchanger (32) is connected to the circulating water insulation kettle (33).

6. A multi-stage continuous cooling crystallization device for acetaminophen according to claim 4, characterized in that: It includes an acylation pump (4) and a five-stage transfer pump (29); the crystallization kettles are provided with five, and the five crystallization kettles include a first-stage crystallization kettle (8), a second-stage crystallization kettle (14), a third-stage crystallization kettle (20), a fourth-stage crystallization kettle (24) and a fifth-stage crystallization kettle (28); The feed port of the acylation pump (4) is connected to the discharge port of the acylation kettle (3) through a pipeline, and the discharge port of the acylation pump (4) is connected to the feed port of the primary crystallization kettle (8) through a pipeline; The feed port of the five-stage transfer pump (29) is connected to the discharge port of the five-stage crystallization kettle (28) through a pipeline, and the discharge port of the five-stage transfer pump (29) is connected to the feed port of the centrifuge (30) through a pipeline.

7. A multi-stage continuous cooling crystallization device for acetaminophen according to claim 6, characterized in that: The invention comprises a primary heat exchanger (10) and a primary reflux detector (9), wherein the primary crystallization kettle (8) and the primary heat exchanger (10) are connected via a pipeline, and the primary reflux detector (9) is installed on the pipeline between the primary crystallization kettle (8) and the primary heat exchanger (10); The primary heat exchanger (10) is used to condense mixed steam of water and glacial acetic acid.

8. A multi-stage continuous cooling crystallization device for acetaminophen according to claim 7, characterized in that: The invention comprises a secondary heat exchanger (16) and a secondary reflux detector (15), wherein the secondary crystallization kettle (14) is connected to the secondary heat exchanger (16) via a pipeline, and the secondary reflux detector (15) is installed on the pipeline between the secondary crystallization kettle (14) and the secondary heat exchanger (16).

9. A multi-stage continuous cooling crystallization device for acetaminophen according to claim 4, characterized in that: A plurality of baffles (31) are installed on the inner wall of each crystallization kettle, and the baffles (31) are evenly arranged around the inner wall of the crystallization kettle.

10. A multi-stage continuous cooling crystallization device for acetaminophen according to claim 4, characterized in that: The material conveying mechanism includes a transfer pump, a first pipeline and a second pipeline, one end of the first pipeline is connected to the discharge port of a crystallization kettle, and the other end thereof is connected to the feed port of the transfer pump, and one end of the second pipeline is connected to the discharge port of the transfer pump, and the other end thereof is connected to the feed port of another crystallization kettle.

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