CN111170880A - Production system and method of acetaminophen - Google Patents
Production system and method of acetaminophen Download PDFInfo
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- CN111170880A CN111170880A CN202010011572.5A CN202010011572A CN111170880A CN 111170880 A CN111170880 A CN 111170880A CN 202010011572 A CN202010011572 A CN 202010011572A CN 111170880 A CN111170880 A CN 111170880A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/22—Separation; Purification; Stabilisation; Use of additives
- C07C231/24—Separation; Purification
Abstract
The invention belongs to the field of preparation of organic chemical intermediate products, and particularly relates to a production system and a production method of acetaminophen. The production system includes: a nitrogen storage device, a batching device, an acylation device, a crystallization device and a recrystallization device; the method comprises the following steps: dissolving the prepared materials, carrying out acylation reaction, carrying out acylation and acid collection, crystallizing and recrystallizing. The method adopts the undried p-aminophenol after refining as the raw material to immediately produce the p-aminophenol by acylation, simplifies the drying procedure of the refined p-aminophenol, saves the steam consumption, reduces the labor intensity and improves the production benefit; the acylation reaction does not need to add a catalyst, and the p-aminophenol and the glacial acetic acid are directly subjected to the acylation reaction, so that the production cost can be saved.
Description
Technical Field
The invention belongs to the field of preparation of organic chemical intermediate products, and particularly relates to a production system and a production method of acetaminophen.
Background
Para-aminophenol, also known as hydroxyaniline, p-hydroxyaniline, abbreviated as PAP, is a colorless or yellowish flaky or needle crystal; turn brown on exposure to light or in air, dissolve in hot water and alcohol, are slightly soluble in cold water, and are practically insoluble in benzene and chloroform. PAP is a very widely used fine organic chemical intermediate: in the medical and pharmaceutical industry, the method is mainly used for synthesizing medicaments such as acetaminophen, paracetamol, clofibrate, vitamin B, compound nicotinamide and the like.
Acetaminophen (Paracetamol), abbreviated as APAP, otherwise known as Tylenol (Tylenol), binaphthol (Panadol), bupernin (bufferine), Paracetamol, as white crystals or crystalline powders, without bad smell and slightly bitter taste. Can be used for treating common cold, fever, arthralgia, neuralgia, migraine, cancer pain, and postoperative pain. The product can also be used for patients allergic to aspirin, intolerant to aspirin, or those who are not suitable for aspirin (varicella, hemophilia, and other hemorrhagic diseases).
In the process of producing p-acetaminophenol by using p-aminophenol, p-aminophenol is used as a raw material to perform acylation reaction with glacial acetic acid after the processes of refining and centrifuging, drying, screening, packaging and the like are performed on a wet product, and then the p-aminophenol is prepared. Because the dry and powdery p-aminophenol is used, the steam is consumed, the cost is increased, the labor intensity is increased, and dust is easily generated to pollute the environment. If the crude p-aminophenol product after the hydrogenation reaction is directly used as a raw material, the quality of the product p-acetaminophen is directly influenced because the crude p-aminophenol product is easily oxidized, discolored and deteriorated due to more aminophenol impurities.
Therefore, in the field of acetaminophen production, it is necessary to develop a method for producing purified acetaminophen without drying and then acylating it, so that the production process is simple, the production process is environment-friendly, and high quality of acetaminophen can be ensured.
Disclosure of Invention
The invention aims to overcome the defects in the prior art and provides a system and a method for producing acetaminophen.
The purpose of the invention is realized by the following technical scheme:
a production system for acetaminophen, the production system comprising: a nitrogen storage device, a batching device, an acylation device, a crystallization device and a recrystallization device;
the nitrogen storage device is used for storing nitrogen and is connected with a pipeline between the batching device and the acylation device or/and the batching device or/and the acylation device so as to keep the air in the batching device, the acylation device and the pipeline between the batching device and the acylation device replaced by the nitrogen;
the batching device is used for forming raw material mixed liquor by the p-aminophenol, the antioxidant and the dilute acid;
the acylation device is connected with the batching device and used for receiving the raw material mixed liquor and realizing acylation reaction and acylation acid extraction treatment to obtain a solid material and an acid liquor; the crystallization device is connected with the acylation device and is used for carrying out crystallization treatment, centrifugal treatment and washing treatment on the solid material to obtain a paracetamol crude product and acylation mother liquor;
and the recrystallization device is connected with the crystallization device and is used for carrying out recrystallization treatment, decoloration and oxidation resistance treatment, filtration treatment, centrifugation treatment and drying treatment on the acetaminophen crude product to obtain an acetaminophen product.
In a preferred embodiment, an acid liquor outlet of the acylation device is connected with an acid liquor return port of the dosing device, and is used for sending the acid liquor into the dosing device for recycling; preferably, a liquid outlet of the crystallization device is connected with an acid liquid reflux port of the batching device, and is used for sending the acylation mother liquor to the batching device for recycling.
A production method of acetaminophen is characterized in that: the method comprises the following steps:
a material preparation and dissolution step: dissolving p-aminophenol in dilute acid in nitrogen atmosphere, and adding an antioxidant to mix uniformly to form a raw material mixed solution;
and (3) acylation reaction: carrying out acylation reaction by taking p-aminophenol and glacial acetic acid in the raw material mixed solution as reactants under the nitrogen atmosphere to obtain an acylation reaction product; no catalyst is added in the acylation reaction;
and (3) acylation and acid collection: carrying out acid collection treatment on the acylation reaction product to obtain an acid solution and a solid material; preferably, the acid liquor is recycled as dilute acid for the stock dissolving step;
a crystallization step: carrying out crystallization treatment, separation treatment and washing treatment on the solid material to obtain a crude acetaminophen product and an acylation mother liquor; preferably, the acylation mother liquor is reused as dilute acid for the stock dissolving step;
a recrystallization step: and (3) carrying out recrystallization treatment, decoloring and antioxidation treatment, filtering treatment, centrifuging treatment and drying treatment on the acetaminophen crude product to obtain an acetaminophen product.
In a preferred embodiment, in the stock material dissolving step, the water content of the p-aminophenol is 3.0% to 5.0%, and the purity is 99.5% to 99.9%.
In a preferred embodiment, in the step of dissolving the prepared material, the mass ratio of the p-aminophenol to the dilute acid is 1 (1-3), preferably 1 (1-1.5), and the mass ratio of the p-aminophenol to the antioxidant is 1 (0.005-0.01); preferably, the antioxidant is the antioxidant sodium metabisulfite.
In a preferred embodiment, in the acylation reaction step, the molar ratio of the p-aminophenol to glacial acetic acid is 1 (1-1.5).
In a preferred embodiment, in the step of acid recovery by acylation, the temperature of the acid recovery treatment is 100 ℃ to 150 ℃.
In a preferred embodiment, in the step of acid collection by acylation, the acid collection treatment is finished when the mass of the obtained acid solution is 0.16 to 0.42 times of the mass of p-aminophenol.
In a preferred embodiment, in the recrystallization step, the crude acetaminophen product is dissolved with pure water at high temperature in the recrystallization treatment and the decolorization and oxidation resistance treatment, and a decolorizer and an antioxidant are added and boiled for 20 to 40 minutes, preferably 30 minutes; the mass ratio of the acetaminophen crude product to the pure water, the decolorizing agent and the antioxidant is 1 (1.5-2.0): (0.02-0.07): 0.01-0.05); preferably, the decolorizing agent is activated carbon, and the antioxidant is sodium metabisulfite.
Compared with the prior art, the invention has the following beneficial effects:
1. the invention adopts the undried p-aminophenol after refining as the raw material to produce the p-aminophenol by acylation, simplifies the drying procedure of the refined p-aminophenol, saves the steam consumption, reduces the labor intensity and improves the production benefit.
2. The invention adopts the refined and purified p-aminophenol as the raw material, compared with the acylation immediately after the hydrogenation reaction is finished, the p-aminophenol has high purity, less impurities and difficult oxidation and discoloration, and the produced product p-acetaminophen has higher quality and better quality.
3. The acylation reaction of the invention does not need to add a catalyst, and the p-aminophenol and the glacial acetic acid are directly subjected to the acylation reaction, so that the production cost can be saved.
4. The acid liquor of the acylation device and the acylation mother liquor of the crystallization device can be reused in the batching device, so that the consumption of dilute acid is saved, and the production cost is saved.
5. The invention adopts acetic acid as acylation raw material, but does not adopt acetic anhydride, because the acetic anhydride is a product which is easy to prepare toxin.
6. The steps and parameters of the invention are directly matched and cooperated with each other, so that the production efficiency is further improved.
Drawings
FIG. 1 is a schematic view of a production system of acetaminophen according to the present invention.
Labels in fig. 1: 1: nitrogen storage device, 2: dosing unit, 3: acylation apparatus, 4: crystallization device, 5: recrystallization apparatus, 6: acid liquor pipeline, 7: acylation mother liquor pipeline.
FIG. 2 is a process flow diagram of the production process of example 1.
Detailed Description
In a first aspect, the present invention provides a system for producing acetaminophen. As shown in fig. 1, the production system of the present invention includes: a nitrogen storage device, a nitrogen tank 1, a batching device, a dissolving kettle 2, an acylation device, an acylation kettle 3, an acid liquor pipeline 6, a crystallizing device 4 (comprising a crystallizing tank, a centrifugal machine or a filter press, which are not respectively shown), an acylation mother liquor pipeline 7 and a recrystallizing device 5 (comprising a recrystallizing tank, a centrifugal machine and a drying machine, which are not respectively shown).
The nitrogen tank 1 is used for storing nitrogen and is connected with a pipeline between the dissolving kettle 2 and the acylation kettle 3, or/and is connected with the dissolving kettle 2, or/and is connected with the acylation kettle 3; preferably only to the line connecting the dissolution tank 2 and the acylation tank 3 as shown in FIG. 1.
And the dissolving kettle 2 is used for forming raw material mixed liquor by the p-aminophenol, the antioxidant and the dilute acid.
The acylation kettle 3 is connected with the dissolving kettle 2 and is used for receiving the raw material mixed solution, carrying out acylation reaction with glacial acetic acid and carrying out acylation and acid collection treatment to obtain a collected solid material and an acid solution; preferably, the other port of the acylation kettle 3 is also connected with the dissolving kettle 2 through an acid liquor pipeline 7 for sending the acid liquor into the dissolving kettle 2 for recycling.
A crystallization device 4 connected to the acylation reactor 3, for crystallizing the solid material in a crystallization tank (not shown), centrifuging the crystallized material by a centrifuge (not shown) or filter-pressing the crystallized material by a filter-pressing device (not shown), and washing the crystallized material by a washing device (not shown) to obtain a crude acetaminophen product and an acylation mother liquor; preferably, the other port of the crystallization device 4 is also connected with the dissolving kettle 2 through an acylation mother liquor pipeline 8, and the acylation mother liquor is sent to the dissolving kettle 2 for recycling.
And a recrystallization device 5 connected to the crystallization device 4, for subjecting the crude acetaminophen product to a decoloring and antioxidation treatment in a recrystallization tank (not shown), a filtration treatment by a filtration device (not shown), a centrifugation treatment by a centrifuge (not shown), and a drying treatment by a drying device (not shown) to obtain an acetaminophen product.
In a second aspect, the present invention provides a process for producing acetaminophen. The method for preparing p-aminophenol using the reaction system of fig. 1 comprises the steps of:
step one, dissolving prepared materials: .
Weighing p-aminophenol, adding the weighed p-aminophenol into a dissolving kettle 2 (a preparation kettle), adding dilute acid to dissolve the p-aminophenol, stirring the mixture evenly to form a p-aminophenol dissolved solution for later use, and adding an antioxidant in the dissolving kettle 2 to obtain a raw material mixed solution.
The content of the p-aminophenol is 95 to 97 percent (wt), the water content is 3.0 to 5.0 percent (wt) (for example, 3.0 percent, 3.5 percent, 4.0 percent, 4.5 percent and 5 percent), and the purity is 99.5 to 99.9 percent; refined, but not dried, p-aminophenol may be used.
The mass ratio of the p-aminophenol to the dilute acid is 1 (1 to 3) (for example, 1:1, 1:1.2, 1:1.3, 1:1.4, 1:2, 1:2.5, 1:2.8, 1:3), and preferably 1: (1-1.5), if the amount of the added dilute acid is too small, the solvent is reduced, the p-aminophenol is not easy to dissolve, the concentration of the generated product is too high, and the product is not easy to centrifuge; if the amount of the dilute acid added is too large, the product generated is dissolved in the dilute acid, which causes the reduction of the product yield. The mass ratio of the p-aminophenol to the antioxidant is 1 (0.005-0.01) (for example, 1:0.005, 1:0.006, 1:0.007, 1:0.008, 1:0.009, 1:0.01) and if the amount of the antioxidant is too small, the raw material p-aminophenol is oxidized, and the antioxidant is increased, which increases the cost; the antioxidant is preferably sodium metabisulfite. For example: 1900kg of p-aminophenol, 2000-4000kg of dilute acid and 9.5-19kg of sodium metabisulfite are added.
When the reaction system operates for the first time in each batch, acid liquor and acylation mother liquor are not generated, and the adopted diluted acid is preferably aqueous solution of glacial acetic acid, wherein the mass concentration of the glacial acetic acid is 50-64% (for example, 50%, 52%, 55%, 58%, 60% and 64%), and the glacial acetic acid and water are uniformly mixed to prepare the diluted acid. And then recycling the acid solution obtained in the third step and the acylation mother liquor obtained in the fourth step to the dissolution kettle 2 to be used as dilute acid.
The air in the dissolving tank 2 is completely replaced by nitrogen, and the antioxidant is added into the dissolving tank 2 to prevent the p-aminophenol from being oxidized.
Step two, acylation reaction: the raw material mixture is conveyed to the acylation reactor 3 by a pump (not shown), and under a nitrogen atmosphere, aminophenol and glacial acetic acid in the raw material mixture are heated and refluxed as reactants to perform an acylation reaction (shown in formula I), so as to obtain an acylation reaction product.
The acylation reaction does not need to add a catalyst, and the p-aminophenol and the glacial acetic acid are directly subjected to the acylation reaction, so that the production cost can be saved.
The molar ratio of the p-aminophenol to glacial acetic acid is 1 (1-1.5) (for example, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1: 1.5). For example: 1500kg of glacial acetic acid were added.
Above-mentioned acylation cauldron 3 is connected with nitrogen storage tank 1, so dissolve cauldron 2, acylation cauldron 3, connect the air in the pipeline between dissolving cauldron 2 and the acylation cauldron 3 and have been replaced for nitrogen gas completely, can prevent that aminophenol from being oxidized.
Step three, acidylation and acid collection: in the acylation kettle 3, the temperature of the acylation reaction product is kept at 100-150 ℃ (for example, 100 ℃, 110 ℃, 120 ℃, 125 ℃, 130 ℃, 140 ℃ and 150 ℃) for acid collection treatment for 3-4 h until the mass ratio of the p-aminophenol to the collected acid liquid reaches 1 (0.16-0.42) (for example, 1:0.16, 1:0.18, 1:0.20, 1:0.25, 1:0.30, 1:0.35, 1:0.40 and 1:0.42), for example, the acid liquid reaches 300-800 kg, and acid liquid and solid materials are obtained; the acid liquor as diluted acid enters the dissolving kettle 2 through a diluted acid pipeline 6 and is reused for the step of dissolving the prepared materials. Preferably, the starting temperature of the acid collecting treatment is 100 ℃, and the temperature is raised to above 118 ℃ after all water is evaporated, preferably to 150 ℃; preferably, in order to avoid the extraction of acetic acid without complete reaction, the acid extraction is slowly started, the temperature is kept at 100 ℃ for 2 hours in a reflux state, the temperature is raised after all water is evaporated, and when the temperature reaches 150 ℃, the temperature is kept until the acid extraction is reached, namely the acid extraction is finished.
The temperature of the acid collection treatment of the acylation reaction product is selected to be 100-150 ℃, because the acylation reaction product and water are generated, the water needs to be distilled out to ensure the complete acylation reaction, the reaction is carried out towards the right, the temperature is not too high when the water is distilled, the temperature is 100 ℃, when the generated water is completely distilled out, the redundant glacial acetic acid needs to be distilled out to ensure the dilute acid concentration of the acylation mother liquor, but the boiling point of the acid is 118 ℃, the temperature needs to be raised, the acetic acid amount is reduced at the later stage of acid collection, the required temperature is higher and is 150 ℃; the temperature is too low, the acid collecting speed is slow, the temperature is too high, the acid collecting speed is high, the acylation reaction is incomplete, and the number of byproducts is increased.
And when the acid collection reaches a certain amount, the acid collection is finished. The acid collection amount is too large, the concentration of the dilute acid in the acylation mother liquor is increased, the acid collection amount is too small, and the generated water cannot be evaporated in time, so that the acylation reaction is influenced to be carried out rightwards.
Step four, crystallization: pumping the solid material into a crystallizing tank (not shown) for cooling to crystallize, separating when the temperature is reduced to room temperature to obtain a wet product and an acylation mother liquor, wherein the separation treatment can be solid-liquid separation after centrifugal high-speed rotation by a centrifugal machine (not shown) or filter pressing by a filter press (not shown), and washing the wet product for 2-3 times by washing equipment to obtain a crude product of acetaminophen; the acylation mother liquor enters the dissolving kettle 2 through an acylation mother liquor pipeline 7 and is also used as dilute acid for the stock dissolving step.
Step five, recrystallization: and (3) sending the acetaminophen crude product into a recrystallization tank (not shown) for recrystallization treatment, decoloring and antioxidation treatment, filtering with a filtering device (not shown) while the acetaminophen crude product is hot, cooling the filtrate to room temperature, centrifuging with a centrifuge (not shown), and drying with a dryer to obtain an acetaminophen product.
In the decolorization and antioxidation treatment, the acetaminophen crude product is dissolved by pure water at high temperature, and a decolorizer and an antioxidant are added, and the boiling state is kept for 20 to 40 minutes, such as 20 minutes, 25 minutes, 35 minutes and 40 minutes, preferably 30 minutes; the mass ratio of the acetaminophen crude product to the pure water, the decolorizing agent and the antioxidant is 1 (1.5-2.0): (0.02-0.07): 0.01-0.05); illustratively, the mass ratio of the crude acetaminophen to the pure water, the decoloring agent and the antioxidant can be as follows: 1:1.5:0.02:0.01, 1:2.0:0.07:0.05, 1:1.5:0.07:0.05, 1:2.0:0.02:0.01, 1:2.0:0.02:0.05, 1:1.8:0.05:0.03, 1:1.7:0.03: 0.04; if the amount of the pure water is increased, steam is wasted when the pure water is heated to a boiling state, and the yield of the product is reduced due to the increase of the amount of the water, but the purity of the product can be improved due to the increase of the amount of the water; if the water amount is reduced, part of impurities in the crude product are still wrapped in the product, so that the quality of the product is reduced, but the water amount is reduced, so that the product yield can be improved; if the decolorant is reduced, adsorbed impurities are reduced, the product quality is reduced, the decolorant is increased, the adsorbed impurities are increased, the product quality is increased, but the decolorant is solid hazardous waste and needs to be treated by qualified units, so that the treatment cost is increased; if the antioxidant is reduced, there is a risk that the product will be oxidized, the antioxidant is increased, the cost of the product will be increased, and the salt in the product will be increased. Preferably, the decolorizing agent is activated carbon and the antioxidant is sodium metabisulfite. For example: 3000-4000kg of pure water, 50-180kg of active carbon and 20-130kg of sodium metabisulfite.
The present invention will be further described with reference to the following examples. It should be understood that these examples are only for the purpose of the present invention and are not intended to limit the scope of the present invention. It should be understood that various changes and modifications can be made by those skilled in the art after reading the disclosure of the present invention, and equivalents fall within the scope of the appended claims.
Example 1
The reaction system used in the method for producing acetaminophen of this example is shown in FIG. 1.
The production method of this example includes the following steps:
(1) preparing materials and dissolving: 1900kg of p-aminophenol with the content of 96% and the purity of 99.62%, 2500kg of dilute acid (glacial acetic acid water solution with the mass concentration of 58%), and 9.5kg of sodium metabisulfite (mass ratio: 1: 1.32: 0.005) are put into a material preparation dissolving kettle and mixed uniformly to obtain a raw material mixed solution for later use.
(2) Acylation reaction: conveying the raw material mixed solution to an acylation kettle through a pump, adding 1253kg of glacial acetic acid (the molar ratio of the undried p-aminophenol to the glacial acetic acid is 1: 1.2) into the acylation kettle (the pipeline, the dissolution kettle and the acylation kettle are replaced by nitrogen), slowly heating to about 100 ℃, and refluxing for 3 hours to obtain an acylation reaction product.
(3) And (3) acylation and acid collection: and (3) carrying out acid collection treatment on the acylation product (reaction liquid): the temperature of starting acid collection is 100 ℃, acid collection is carried out slowly, the temperature is raised to 150 ℃ after water is completely evaporated, and acid collection is finished when the acid collection amount is 502kg (wherein the mass concentration of acetic acid is 40%), so that acid liquor and solid materials are obtained. Wherein the acid liquor enters the dissolution kettle for recycling.
(4) And (3) crystallization: the solid material is injected into a crystallizing tank, cooled and crystallized, and when the temperature is reduced to room temperature, the solid material is centrifuged to obtain a wet product and acylation mother liquor; and washing the wet product with water for 2-3 times to obtain a crude product of the acetaminophen. The acylation mother liquor enters a dissolving kettle for recycling.
(5) And (3) recrystallizing a crude product: and dissolving 2400kg of the obtained crude product with 3600kg of pure water at high temperature, adding 100kg of active carbon and 50kg of sodium metabisulfite at the same time, boiling for 30 minutes, filtering while hot, cooling the filtrate to room temperature, centrifuging, and drying to obtain a refined acetaminophen product.
The refined acetaminophen product is screened and packaged to obtain an acetaminophen finished product.
Through inspection, the content of the refined acetaminophen product is 99.74%, the product yield can reach 91.0%, and the product meets the standard of Chinese pharmacopoeia 2015 edition.
The above yield was calculated as follows: the yield was (finished product mass/(mass of p-aminophenol × 1.3852)) × 100%, the finished product mass in the molecule was the mass of the purified p-acetaminophen product obtained in step (5), and the p-aminophenol in the denominator was the mass of the p-aminophenol in step (1).
Example 2
The reaction system used in the method for producing acetaminophen of this example is shown in FIG. 1.
The production method of this example includes the following steps:
(1) preparing materials and dissolving: 1900kg of p-aminophenol with the content of 97 percent and the purity of 99.78 percent, 2500kg of dilute acid (glacial acetic acid water solution with the mass concentration percentage of 50 percent) and 9.5kg of sodium metabisulfite (mass ratio: 1: 1.32: 0.005) are put into a material preparation dissolving kettle and are mixed uniformly to obtain a raw material mixed solution for later use.
(2) Acylation reaction: conveying the raw material mixed solution to an acylation kettle through a pump, adding 1464kg of glacial acetic acid (the molar ratio of undried p-aminophenol to glacial acetic acid is 1: 1.3) into a pipeline, a dissolving kettle and the acylation kettle, replacing air in the acylation kettle with nitrogen, slowly heating to about 110 ℃, and refluxing for 3 hours to obtain an acylation reaction product.
(3) And (3) acylation and acid collection: and (3) carrying out acid collection treatment on the acylation product (reaction liquid): the temperature of starting acid collection is 100 ℃, acid collection is slowly carried out, the temperature is raised to 150 ℃ after water is completely evaporated, acid collection is finished when the acid collection amount is 628kg (wherein the mass concentration of acetic acid is 51.5 percent), and acid liquor and solid materials are obtained. Wherein the acid liquor enters the dissolution kettle for recycling.
(4) And (3) crystallization: the solid material is injected into a crystallizing tank, cooled and crystallized, and when the temperature is reduced to room temperature, the solid material is centrifuged to obtain a wet product and acylation mother liquor; and washing the wet product with water for 2-3 times to obtain a crude product of the acetaminophen. The acylation mother liquor enters a dissolving kettle for recycling.
(5) And (3) recrystallizing a crude product: dissolving 2428kg of the crude product with 3642kg of pure water at high temperature, adding 100kg of active carbon and 50kg of sodium metabisulfite, boiling for 30 minutes, filtering while hot, cooling the filtrate to room temperature, centrifuging, and drying to obtain a refined acetaminophen product.
Through inspection, the content of the refined acetaminophen product is 99.60%, the product yield can reach 91.2%, and the product meets the standard of Chinese pharmacopoeia 2015 edition.
Example 3
The reaction system used in the method for producing acetaminophen of this example is shown in FIG. 1.
The production method of this example includes the following steps:
(1) preparing materials and dissolving: 1900kg of p-aminophenol with the content of 96.5% and the purity of 99.68%, 2500kg of dilute acid (glacial acetic acid water solution with the mass concentration of 64%), and 9.5kg of sodium metabisulfite (mass ratio: 1: 1.32: 0.005) are put into a material preparation dissolving kettle and mixed uniformly to obtain a raw material mixed solution for later use.
(2) Acylation reaction: conveying the raw material mixed solution to an acylation kettle through a pump, adding 1464kg of glacial acetic acid (the molar ratio of undried p-aminophenol to glacial acetic acid is 1: 1.4) into a pipeline, a dissolving kettle and the acylation kettle, replacing air in the acylation kettle with nitrogen, slowly heating to about 110 ℃, and refluxing for 3 hours to obtain an acylation reaction product.
(3) And (3) acylation and acid collection: and (3) carrying out acid collection treatment on the acylation product (reaction liquid): the temperature of starting acid collection is 100 ℃, acid collection is slowly carried out, the temperature is raised to 150 ℃ after water is completely evaporated, acid collection is finished when the acid collection amount is 624kg (wherein the mass concentration of acetic acid is 51.6 percent), and acid liquor and solid materials are obtained. Wherein the acid liquor enters the dissolution kettle for recycling.
(4) And (3) crystallization: the solid material is injected into a crystallizing tank, cooled and crystallized, and when the temperature is reduced to room temperature, the solid material is centrifuged to obtain a wet product and acylation mother liquor; and washing the wet product with water for 2-3 times to obtain a crude product of the acetaminophen. The acylation mother liquor enters a dissolving kettle for recycling.
(5) And (3) recrystallizing a crude product: 2415kg of crude product is dissolved by 3623kg of pure water at high temperature, 100kg of active carbon and 50kg of sodium metabisulfite are added at the same time, the mixture is boiled for 30 minutes, the hot mixture is filtered, the filtrate is cooled to room temperature, and the refined acetaminophen product is obtained by centrifugation and drying.
Through inspection, the content of the refined acetaminophen product is 99.58%, the product yield can reach 91.8%, and the product meets the standard of Chinese pharmacopoeia 2015 edition.
Example 4
The reaction system used in the method for producing acetaminophen of this example is shown in FIG. 1.
The production method of this example includes the following steps:
(1) preparing materials and dissolving: 1900kg of p-aminophenol with the content of 96.9 percent and the purity of 99.87 percent, 2500kg of dilute acid (glacial acetic acid water solution with the mass concentration of 60 percent) and 9.5kg of sodium metabisulfite (mass ratio: 1: 1.32: 0.005) are put into a material preparation dissolving kettle and are mixed uniformly to obtain a raw material mixed solution for later use.
(2) Acylation reaction: conveying the raw material mixed solution to an acylation kettle through a pump, adding 1464kg of glacial acetic acid (the molar ratio of undried p-aminophenol to glacial acetic acid is 1: 1.4) into a pipeline, a dissolving kettle and the acylation kettle, replacing air in the acylation kettle with nitrogen, slowly heating to about 110 ℃, and refluxing for 3 hours to obtain an acylation reaction product.
(3) And (3) acylation and acid collection: and (3) carrying out acid collection treatment on the acylation product (reaction liquid): the temperature of starting acid collection is 100 ℃, acid collection is slowly carried out, the temperature is raised to 150 ℃ after water is completely evaporated, acid collection is finished when the acid collection amount is 628kg (wherein the mass concentration of acetic acid is 51.6 percent), and acid liquor and solid materials are obtained. Wherein the acid liquor enters the dissolution kettle for recycling.
(4) And (3) crystallization: the solid material is injected into a crystallizing tank, cooled and crystallized, and when the temperature is reduced to room temperature, the solid material is centrifuged to obtain a wet product and acylation mother liquor; and washing the wet product with water for 2-3 times to obtain a crude product of the acetaminophen. The acylation mother liquor enters a dissolving kettle for recycling.
(5) And (3) recrystallizing a crude product: dissolving 2425kg of the crude product with 3638kg of pure water at high temperature, adding 100kg of active carbon and 50kg of sodium metabisulfite, boiling for 30 minutes, filtering while hot, cooling the filtrate to room temperature, centrifuging, and drying to obtain the refined acetaminophen product.
Through inspection, the content of the refined acetaminophen product is 99.68%, the product yield can reach 91.5%, and the product conforms to the standard of Chinese pharmacopoeia 2015 edition.
Example 5
The reaction system used in the method for producing acetaminophen of this example is shown in FIG. 1.
The production method of this example includes the following steps:
(1) preparing materials and dissolving: 1900kg of p-aminophenol with the content of 96% and the purity of 99.62%, 1900kg of dilute acid (glacial acetic acid water solution with the mass concentration percentage of 58%), and 19kg of sodium metabisulfite (mass ratio: 1: 1:0.01) are put into a material preparation dissolving kettle and mixed uniformly to obtain a raw material mixed solution for later use.
(2) Acylation reaction: conveying the raw material mixed solution to an acylation kettle through a pump, adding 1047kg of glacial acetic acid (the molar ratio of undried p-aminophenol to glacial acetic acid is 1: 1) into a pipeline, a dissolving kettle and the acylation kettle, replacing air in the acylation kettle with nitrogen, slowly heating to about 100 ℃, and refluxing for 3 hours to obtain an acylation reaction product.
(3) And (3) acylation and acid collection: and (3) carrying out acid collection treatment on the acylation product (reaction liquid): the temperature of starting acid collection is 100 ℃, acid collection is carried out slowly, the temperature is raised to 150 ℃ after water is completely evaporated, and acid collection is finished when the acid collection amount is 300kg (wherein the mass concentration of acetic acid is 10 percent), so that acid liquor and solid materials are obtained. Wherein the acid liquor enters the dissolution kettle for recycling.
(4) And (3) crystallization: the solid material is injected into a crystallizing tank, cooled and crystallized, and when the temperature is reduced to room temperature, the solid material is centrifuged to obtain a wet product and acylation mother liquor; and washing the wet product with water for 2-3 times to obtain a crude product of the acetaminophen. The acylation mother liquor enters a dissolving kettle for recycling.
(5) And (3) recrystallizing a crude product: and dissolving the obtained crude product 2279kg with 3418kg of pure water at high temperature, adding 110kg of active carbon and 45kg of sodium metabisulfite, boiling for 30 minutes, filtering while hot, cooling the filtrate to room temperature, centrifuging, and drying to obtain the refined acetaminophen product.
Through inspection, the content of the refined acetaminophen product is 99.48%, the product yield can reach 89.5%, and the product meets the standard of Chinese pharmacopoeia 2015 edition.
Example 6
The reaction system used in the method for producing acetaminophen of this example is shown in FIG. 1.
The production method of this example includes the following steps:
(1) preparing materials and dissolving: 1900kg of p-aminophenol with the content of 96% and the purity of 99.62%, 2850kg of dilute acid (glacial acetic acid water solution with the mass concentration of 58%), and 15.2kg of sodium metabisulfite (mass ratio: 1:1.5: 0.008) are put into a stock dissolving kettle and mixed uniformly to obtain a raw material mixed solution for later use.
(2) Acylation reaction: conveying the raw material mixed solution to an acylation kettle through a pump, adding 1570kg of glacial acetic acid (the molar ratio of the undried p-aminophenol to the glacial acetic acid is 1:1.5) into the mixture (a pipeline, a dissolving kettle and the acylation kettle are replaced by nitrogen), slowly heating to about 100 ℃, and refluxing for 3 hours to obtain an acylation reaction product.
(3) And (3) acylation and acid collection: and (3) carrying out acid collection treatment on the acylation product (reaction liquid): the temperature of starting acid collection is 100 ℃, acid collection is carried out slowly, the temperature is raised to 150 ℃ after water is completely evaporated, acid collection is finished when the acid collection amount is 800kg (wherein the mass concentration of acetic acid is 63.4%), and acid liquor and solid materials are obtained. Wherein the acid liquor enters the dissolution kettle for recycling.
(4) And (3) crystallization: the solid material is injected into a crystallizing tank, cooled and crystallized, and when the temperature is reduced to room temperature, the solid material is centrifuged to obtain a wet product and acylation mother liquor; and washing the wet product with water for 2-3 times to obtain a crude product of the acetaminophen. The acylation mother liquor enters a dissolving kettle for recycling.
(5) And (3) recrystallizing a crude product: and dissolving 2351kg of the obtained crude product with 3527kg of pure water at high temperature, adding 120kg of active carbon and 48kg of sodium metabisulfite, boiling for 30 minutes, filtering while hot, cooling the filtrate to room temperature, centrifuging, and drying to obtain the refined acetaminophen product.
Through inspection, the content of the refined acetaminophen product is 99.59%, the product yield can reach 90.1%, and the product meets the standard of Chinese pharmacopoeia 2015 edition.
Example 7
The reaction system used in the process for producing acetaminophen of this comparative example is shown in FIG. 1.
The ingredients, the raw material amounts, the operation modes and the parameters adopted in the steps (2) to (5) of the production method of the embodiment are the same as those of the embodiment 1.
In the step (1):
1900kg of p-aminophenol with the content of 96% and the purity of 99.62%, 5700kg of dilute acid (glacial acetic acid water solution with the mass concentration percentage of 58%), and 9.5kg of sodium metabisulfite (mass ratio: 1: 3: 0.005) are put into a material preparation dissolving kettle and mixed uniformly to obtain a raw material mixed solution for later use.
Through inspection, the content of the refined acetaminophen product is 99.68%, and the product yield can reach 89.3%.
Claims (9)
1. A production system of acetaminophen, which is characterized in that: the production system includes:
a nitrogen storage device, a batching device, an acylation device, a crystallization device and a recrystallization device;
the nitrogen storage device is used for storing nitrogen and is connected with a pipeline between the batching device and the acylation device or/and the batching device or/and the acylation device so as to keep the air in the batching device, the acylation device and the pipeline between the batching device and the acylation device replaced by the nitrogen;
the batching device is used for forming raw material mixed liquor by the p-aminophenol, the antioxidant and the dilute acid;
the acylation device is connected with the batching device and used for receiving the raw material mixed liquor and realizing acylation reaction and acylation acid extraction treatment to obtain a solid material and an acid liquor; the crystallization device is connected with the acylation device and is used for carrying out crystallization treatment, centrifugal treatment and washing treatment on the solid material to obtain a paracetamol crude product and an acylation mother liquor;
the recrystallization device is connected with the crystallization device and is used for carrying out recrystallization treatment, decoloration anti-oxidation treatment, filtration treatment, centrifugation treatment and drying treatment on the acetaminophen crude product to obtain an acetaminophen product.
2. The production system according to claim 1, wherein:
an acid liquor outlet of the acylation device is connected with an acid liquor backflow port of the batching device and used for sending the acid liquor into the batching device for recycling;
preferably, a liquid outlet of the crystallization device is connected with an acid liquid reflux port of the batching device, and is used for sending the acylation mother liquor to the batching device for recycling.
3. A production method of acetaminophen is characterized in that: the method comprises the following steps:
a material preparation and dissolution step: dissolving p-aminophenol in dilute acid in nitrogen atmosphere, and adding an antioxidant to mix uniformly to form a raw material mixed solution;
and (3) acylation reaction: carrying out acylation reaction by taking p-aminophenol and glacial acetic acid in the raw material mixed solution as reactants under the nitrogen atmosphere to obtain an acylation reaction product; no catalyst is added in the acylation reaction;
and (3) acylation and acid collection: carrying out acid collection treatment on the acylation reaction product to obtain an acid solution and a solid material; preferably, the acid liquor is recycled as dilute acid for the stock dissolving step;
a crystallization step: carrying out crystallization treatment, separation treatment and washing treatment on the solid material to obtain a crude acetaminophen product and an acylation mother liquor; preferably, the acylation mother liquor is reused as dilute acid for the stock dissolving step;
a recrystallization step: and (3) carrying out recrystallization treatment, decoloring and antioxidation treatment, filtering treatment, centrifuging treatment and drying treatment on the acetaminophen crude product to obtain an acetaminophen product.
4. The production method according to claim 3, characterized in that: in the step of dissolving the prepared materials, the water content of the p-aminophenol is 3.0-5.0%, and the purity of the p-aminophenol is 99.5-99.9%.
5. The production method according to claim 3, characterized in that: in the step of dissolving the stock preparation,
the mass ratio of the p-aminophenol to the dilute acid is 1 (1-3), preferably 1 (1-1.5), and the mass ratio of the p-aminophenol to the antioxidant is 1 (0.005-0.01); preferably, the antioxidant is the antioxidant sodium metabisulfite.
6. The production method according to claim 3, characterized in that: in the acylation reaction step, the molar ratio of the p-aminophenol to the glacial acetic acid is 1 (1-1.5).
7. The production method according to claim 3, characterized in that: in the step of acidylation and acid collection, the temperature of acid collection treatment is 100-150 ℃.
8. The production method according to claim 3, characterized in that: and in the step of acidylating and collecting acid, acid collecting treatment is finished when the mass of the obtained acid liquor is 0.16-0.42 times of that of the p-aminophenol.
9. The production method according to claim 3, characterized in that: in the step of recrystallization, in the step of recrystallization and the step of decoloration and antioxidation, the crude acetaminophen product is dissolved by pure water at high temperature, and a decolorant and an antioxidant are added, and the mixture is boiled for 20 to 40 minutes, preferably for 30 minutes; the mass ratio of the acetaminophen crude product to the pure water, the decolorizing agent and the antioxidant is 1 (1.5-2.0): (0.02-0.07): 0.01-0.05); preferably, the decolorizing agent is activated carbon, and the antioxidant is sodium metabisulfite.
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Cited By (2)
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| CN115872885A (en) * | 2022-11-25 | 2023-03-31 | 河北冀衡药业股份有限公司 | Preparation method of acetaminophen by controlling content of acetaminophen impurity N |
| CN115894271A (en) * | 2022-11-25 | 2023-04-04 | 河北冀衡药业股份有限公司 | Preparation method of acetaminophen by controlling content of acetaminophen impurity H |
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