CN112479914B - Device and method for continuously producing acetaminophen - Google Patents
Device and method for continuously producing acetaminophen Download PDFInfo
- Publication number
- CN112479914B CN112479914B CN202011329494.XA CN202011329494A CN112479914B CN 112479914 B CN112479914 B CN 112479914B CN 202011329494 A CN202011329494 A CN 202011329494A CN 112479914 B CN112479914 B CN 112479914B
- Authority
- CN
- China
- Prior art keywords
- acylation
- kettle
- reaction
- acetic acid
- acylation reaction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 title claims abstract description 76
- 229960005489 paracetamol Drugs 0.000 title claims abstract description 45
- 238000000034 method Methods 0.000 title claims abstract description 37
- 238000005917 acylation reaction Methods 0.000 claims abstract description 207
- 230000010933 acylation Effects 0.000 claims abstract description 117
- 238000006243 chemical reaction Methods 0.000 claims abstract description 42
- 238000002360 preparation method Methods 0.000 claims abstract description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 199
- PLIKAWJENQZMHA-UHFFFAOYSA-N 4-aminophenol Chemical compound NC1=CC=C(O)C=C1 PLIKAWJENQZMHA-UHFFFAOYSA-N 0.000 claims description 50
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 19
- 239000000463 material Substances 0.000 claims description 11
- 239000000203 mixture Substances 0.000 claims description 11
- 238000004090 dissolution Methods 0.000 claims description 9
- 238000007599 discharging Methods 0.000 claims description 7
- 238000002156 mixing Methods 0.000 claims description 3
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims description 2
- 238000004064 recycling Methods 0.000 claims description 2
- 238000001953 recrystallisation Methods 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 8
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 238000010924 continuous production Methods 0.000 abstract description 4
- 230000000052 comparative effect Effects 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 238000003860 storage Methods 0.000 description 6
- 239000002253 acid Substances 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 2
- 102000010907 Cyclooxygenase 2 Human genes 0.000 description 2
- 108010037462 Cyclooxygenase 2 Proteins 0.000 description 2
- 208000002193 Pain Diseases 0.000 description 2
- 229960001138 acetylsalicylic acid Drugs 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000036407 pain Effects 0.000 description 2
- 230000002093 peripheral effect Effects 0.000 description 2
- 150000003180 prostaglandins Chemical class 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000013589 supplement Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- HMUNWXXNJPVALC-UHFFFAOYSA-N 1-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C(CN1CC2=C(CC1)NN=N2)=O HMUNWXXNJPVALC-UHFFFAOYSA-N 0.000 description 1
- WZFUQSJFWNHZHM-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)CC(=O)N1CC2=C(CC1)NN=N2 WZFUQSJFWNHZHM-UHFFFAOYSA-N 0.000 description 1
- YJLUBHOZZTYQIP-UHFFFAOYSA-N 2-[5-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-1,3,4-oxadiazol-2-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1=NN=C(O1)CC(=O)N1CC2=C(CC1)NN=N2 YJLUBHOZZTYQIP-UHFFFAOYSA-N 0.000 description 1
- CONKBQPVFMXDOV-QHCPKHFHSA-N 6-[(5S)-5-[[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]methyl]-2-oxo-1,3-oxazolidin-3-yl]-3H-1,3-benzoxazol-2-one Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C[C@H]1CN(C(O1)=O)C1=CC2=C(NC(O2)=O)C=C1 CONKBQPVFMXDOV-QHCPKHFHSA-N 0.000 description 1
- 208000006820 Arthralgia Diseases 0.000 description 1
- 206010058019 Cancer Pain Diseases 0.000 description 1
- 208000005156 Dehydration Diseases 0.000 description 1
- 208000019695 Migraine disease Diseases 0.000 description 1
- 208000000114 Pain Threshold Diseases 0.000 description 1
- 208000004550 Postoperative Pain Diseases 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 239000003907 antipyretic analgesic agent Substances 0.000 description 1
- 238000010923 batch production Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000002267 hypothalamic effect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 206010027599 migraine Diseases 0.000 description 1
- 201000009240 nasopharyngitis Diseases 0.000 description 1
- 208000004296 neuralgia Diseases 0.000 description 1
- 230000037040 pain threshold Effects 0.000 description 1
- 238000011056 performance test Methods 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 230000035900 sweating Effects 0.000 description 1
- 230000028016 temperature homeostasis Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
Images
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a device and a method for continuously producing acetaminophen. According to the preparation method of the acetaminophen, the acylation reaction temperature is limited by the step-by-step acylation reaction, and the temperature of the acylation reaction at the later step is higher than that of the acylation reaction at the former step, so that the acylation rate of the acetaminophen is higher; further, the device and the method for continuously producing the acetaminophen provided by the invention can be suitable for large-scale continuous production, can maximize the utilization rate of raw materials, and have the advantages of higher raw material conversion rate, lower production cost, higher product yield and higher purity.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical engineering, and relates to a device and a method for continuously producing acetaminophen.
Background
Acetaminophen (Paracetamol), known as Paracetamol, is a antipyretic analgesic used for treating common cold with fever, arthralgia, neuralgia and migraine, cancer pain and postoperative pain, and has similar antipyretic effect to aspirin by inhibiting cyclooxygenase-2 (COX-2) to selectively inhibit synthesis of central prostaglandin of hypothalamic thermoregulation, resulting in peripheral vasodilation and sweating; the analgesic composition has the effects of stopping synthesis and release of prostaglandin and the like, improving pain threshold and relieving pain, belongs to peripheral analgesic drugs, has weaker effect than aspirin, is effective on light and moderate pains, and has no obvious anti-inflammatory effect.
At present, a method for preparing acetaminophen by acylating p-aminophenol and acetic acid is generally adopted, but because water is generated in the reaction, if the generated water is not removed in time, the progress of the acylation reaction is slowed down, the reaction is not carried out when the reaction equilibrium is reached, the acylation rate is lower, and the residue of the p-aminophenol is larger. The traditional method adopts a batch production method of once acylation, can not timely remove water generated by reaction, has the defects of high energy consumption, high cost, poor product quality, high labor intensity, low production efficiency and the like.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a device and a method for continuously producing acetaminophen, and the method provided by the invention is suitable for large-scale continuous production, and has the advantages of lower production cost, higher product yield and higher purity.
To achieve the purpose, the invention adopts the following technical scheme:
in a first aspect, the present invention provides a process for the preparation of acetaminophen, the process comprising: carrying out multi-step acylation reaction on the paracetamol and acetic acid to obtain the paracetamol;
wherein the temperature of the acylation reaction is 105-120 ℃, and the temperature of the next step of acylation reaction is higher than that of the previous step of acylation reaction, preferably 1-10 ℃, such as 2 ℃, 3 ℃, 5 ℃, 6 ℃, 7 ℃, 8 ℃, 9 ℃ and the like.
As a preferred embodiment of the present invention, the acylation reaction is a three-step acylation reaction, wherein the first step is carried out at a temperature of 105 to 110℃such as 106℃and 107℃and 108℃and 109℃and the like, the second step is carried out at a temperature of 110 to 115℃such as 111℃and 112℃and 113℃and 114℃and the third step is carried out at a temperature of 115 to 120℃such as 116℃and 117℃and 118℃and 119℃and the like.
The invention improves the acylation rate of the p-aminophenol by a stepwise acylation method, reduces the reaction cost, and simultaneously has higher purity of the finally obtained p-acetaminophen, and can be suitable for industrial continuous production.
The acetaminophen prepared by the invention can be further refined to obtain acetaminophen bulk drug, and the refining process is a conventional process in the prior art and comprises the procedures of heating, dissolving, decoloring, filtering to a clean area, cooling, crystallizing, drying and the like.
In order to further improve the product yield, the acylation rate of the first step of the invention reaches more than 80 percent, the second step of the acylation reaction is carried out, the acylation rate of the second step of the acylation reaction reaches more than 95 percent, and the third step of the acylation reaction is carried out.
The acylation rate refers to the acylation rate of p-aminophenol.
In the process of the acylation reaction, the azeotrope formed by the acetic acid and the water is discharged out of the reaction system and does not flow back into the reaction system.
The water and acetic acid generated by the reaction form an azeotrope, the azeotrope can be discharged out of the reaction system at the temperature of more than 105 ℃, the azeotrope discharged out of the reaction system does not return back into the reaction system any more, but can be collected for rectification, and the purity of the rectified acetic acid is extremely high and can still be reused as a raw material.
In order to ensure the conversion of p-aminophenol, part of the acetic acid is fed in when the first acylation reaction is carried out, preferably the fed acetic acid is fed in an amount of 20-30% by mass, such as 22%, 25%, 26%, 28% by mass, etc., of the mass of p-aminophenol.
In the present invention, in carrying out the second acylation reaction, a part of acetic acid is added, preferably 20 to 30% by mass, for example 22%, 25%, 26%, 28% by mass, etc., of the mass of the para-aminophenol.
In the present invention, when the third step of acylation reaction is carried out, part of acetic acid is supplemented, preferably 20 to 30% by mass, for example 22%, 25%, 26%, 28% by mass, etc., of the mass of p-aminophenol.
In the invention, the mass ratio of the para-aminophenol to the acetic acid is 1 (1.8-2.2), such as 1:1.9, 1:2.0, 1:2.1 and the like, during initial feeding.
The acetic acid is any commercially available acetic acid in the prior art, and the content of the acetic acid is more than 80 percent, so that the application requirement can be met.
In a second aspect, the present invention provides an apparatus for continuously producing acetaminophen, which can realize the preparation method of the first aspect;
the device comprises a primary acylation kettle, a medium-grade acylation kettle and a deep acylation kettle which are sequentially connected, wherein the temperature in the acylation kettle is 105-120 ℃, and the temperature in the subsequent acylation kettle is higher than the temperature in the previous acylation kettle, preferably 1-10 ℃.
As a preferred technical scheme of the invention, the primary acylation kettle is connected with a rectifying tower.
The invention can carry out step-by-step acylation reaction by arranging the primary acylation kettle, the intermediate-grade acylation kettle and the deep acylation kettle, and meanwhile, the arranged rectifying tower can collect the azeotrope discharged during the acylation reaction of the primary acylation kettle, the azeotrope can be rectified in the rectifying tower to recover and refine the acetic acid, and the recovered acetic acid can be reused as a raw material to carry out the next acylation reaction, so that the raw material is saved and the reaction efficiency is improved.
The sequential connection means that the primary acylation kettle is connected with the intermediate-grade acylation kettle, and the intermediate-grade acylation kettle is connected with the deep acylation kettle.
The device also comprises a dissolution kettle, wherein the dissolution kettle is connected with the primary acylation kettle.
As a preferable embodiment of the present invention, the temperature of the dissolution vessel is 70-90 ℃, preferably 72 ℃, 75 ℃, 78 ℃, 80 ℃, 82 ℃, 85 ℃, 88 ℃, etc.
The device also comprises a second connecting device for connecting the primary acylation kettle and the intermediate acylation kettle, wherein an azeotrope in the second step of acylation reaction process carried out by the intermediate acylation kettle enters the primary acylation kettle through the second connecting device to participate in the first step of acylation reaction.
The device also comprises a third connecting device for connecting the intermediate-grade acylation kettle and the deep acylation kettle, wherein an azeotrope in the third-step acylation reaction process carried out by the deep acylation kettle enters the intermediate-grade acylation kettle through the third connecting device to participate in the second-step acylation reaction.
The device also comprises a fourth connecting device connected with the deep acylation kettle, and acetic acid which is needed to be added in the third step of acylation reaction is added through the fourth connecting device.
As a specific embodiment of the invention, the invention further comprises a fifth connecting device connected with the primary acylating kettle, and the primary acylating kettle can directly use the fifth connecting device to supplement acetic acid.
The invention also comprises a sixth connecting device connected with the intermediate-grade acylation kettle, and the intermediate-grade acylation kettle can directly use the sixth connecting device to supplement acetic acid.
The source of additional acetic acid may be acetic acid purchased directly or by distillation from recovered azeotropes.
In the production process, the azeotrope of the third step of acylation reaction can enter the second step of acylation reaction to continue the acylation reaction, the azeotrope of the second step of acylation reaction can enter the first step of acylation reaction to continue the acylation reaction, and meanwhile, the azeotrope of the first step of acylation reaction enters the rectifying tower to recycle acetic acid.
In a third aspect, the present invention provides a process for continuously producing acetaminophen using the apparatus of the second aspect, the process comprising:
after mixing p-aminophenol and acetic acid, sequentially carrying out step-by-step acylation reaction by using a primary acylation kettle, a medium-grade acylation kettle and a deep acylation kettle to obtain the p-acetaminophen;
as a preferred embodiment of the present invention, the method includes:
mixing p-aminophenol and acetic acid, sending the mixture into a primary acylation kettle to carry out a first acylation reaction, sending the mixture into a medium-grade acylation kettle to carry out a second acylation reaction after the acylation rate reaches more than 80%, sending the mixture into a deep acylation kettle to carry out a third acylation reaction after the acylation rate reaches more than 95%, and discharging the mixture after the acylation rate reaches 99.5% to obtain the p-acetaminophen.
As a specific embodiment of the present invention, the method specifically comprises:
(1) Adding the para-aminophenol and acetic acid into a dissolving kettle according to the mass ratio of (1.8-2.2) to be stirred and dissolved at 70-90 ℃;
(2) The dissolved material enters a primary acylation kettle through a conveying and connecting device, a first step of acylation reaction is carried out at 105-110 ℃, water generated by the reaction and acetic acid form an azeotrope, and a rectifying tower is used for recycling;
(3) When the acylation rate of the first acylation reaction reaches more than 80%, feeding the material into a medium-grade acylation kettle for a second-step acylation reaction, wherein the reaction temperature is 110-115 ℃, and an azeotrope formed by water and acetic acid generated by the reaction enters the first-grade acylation kettle through a second connecting device to participate in the first-step acylation reaction;
(4) When the acylation rate of the second acylation reaction reaches more than 95%, feeding the material into a deep acylation kettle, and adding part of acetic acid to perform a third step of acylation reaction, wherein the reaction temperature is 115-120 ℃, and an azeotrope formed by water generated by the reaction and the acetic acid enters a medium-grade acylation kettle through a third connecting device to participate in the second step of acylation reaction;
(5) And discharging after the acylation rate of the third acylation reaction reaches 99.5%, so as to obtain the acetaminophen.
Compared with the prior art, the invention has the following beneficial effects:
according to the preparation method of the acetaminophen, the acylation reaction temperature is limited by the step-by-step acylation reaction, and the temperature of the acylation reaction at the later step is higher than that of the acylation reaction at the former step, so that the acylation rate of the acetaminophen is higher; further, the device and the method for continuously producing the acetaminophen provided by the invention can be suitable for large-scale continuous production, can maximize the utilization rate of raw materials, and have the advantages of higher raw material conversion rate, lower production cost, higher product yield and higher purity.
Drawings
FIG. 1 shows an apparatus for continuously producing acetaminophen provided in example 1 of the present invention.
Wherein, 1-a primary reaction kettle; 2-a medium-grade reaction kettle; 3-deep reaction kettle; 4-rectifying tower; 5-dissolving kettle; 6-a second connection means; 7-a third connecting means; 8-fourth connecting means; 9-fifth connecting means; 10-sixth connecting means; 11-acetic acid storage tank.
Detailed Description
The technical scheme of the invention is further described below by the specific embodiments with reference to the accompanying drawings. It should be apparent to those skilled in the art that the detailed description is merely provided to aid in understanding the invention and should not be taken as limiting the invention in any way.
Example 1
This example provides an apparatus for continuously producing acetaminophen.
Comprises a dissolution kettle 5, a primary acylation kettle 1, a medium-grade acylation kettle 2 and a deep acylation kettle 3 which are connected in sequence, wherein the primary acylation kettle 1 is connected with a rectifying tower 4.
The device also comprises a second connecting device 6, wherein the second connecting device 6 is connected with the primary acylation kettle 1 and the intermediate acylation kettle 2; the device also comprises a third connecting device 7, wherein the third connecting device 7 is connected with the intermediate-grade acylation kettle 2 and the deep acylation kettle 3; and the device also comprises a fourth connecting device 8, and the fourth connecting device 8 is connected with the deep acylation kettle 3.
The device also comprises an acetic acid storage tank 11 which can store acetic acid after rectification by the rectifying tower, a fifth connecting device 9 is connected with the acetic acid storage tank 11 and the primary acylating kettle 1, and a sixth connecting device 10 is connected with the acetic acid storage tank 11 and the intermediate acylating kettle 2.
Example 2
This example provides a process for producing acetaminophen.
(1) 1000kg of p-aminophenol and acetic acid (96%) are put into a dissolution kettle according to a mass ratio of 1:1.8, stirred and dissolved at 72 ℃;
(2) The dissolved material enters a primary acylation kettle through a conveying pipeline, the acylation temperature is controlled at 108 ℃, water generated by the reaction azeotropes with acetic acid, the azeotrope enters a rectifying tower for rectification, the concentration of the rectified acetic acid is more than or equal to 96%, and the rectified acetic acid is stored in an acetic acid storage tank;
(3) When the acylation rate of the first acylation reaction reaches more than 80%, feeding the material into a medium-grade acylation kettle for a second-step acylation reaction, wherein the reaction temperature is 112 ℃, and an azeotrope formed by water and acetic acid generated by the reaction enters the first-step acylation kettle through a second connecting device to participate in the first-step acylation reaction;
(4) When the acylation rate of the second acylation reaction reaches more than 95%, feeding the material into a deep acylation kettle, adding 200kg of acetic acid to perform a third step of acylation reaction, wherein the reaction temperature is 118 ℃, and enabling an azeotrope formed by water generated by the reaction and the acetic acid to enter a medium-grade acylation kettle through a third connecting device to participate in the second step of acylation reaction;
(5) And discharging after the acylation rate of the third acylation reaction reaches 99.5%, so as to obtain the acetaminophen.
Examples 3 to 6
This example provides a process for producing acetaminophen.
The difference from example 2 is that the additives are added in the proportions indicated in Table 1:
TABLE 1
| Mass ratio of para-aminophenol to acetic acid | Adding acetic acid mass/kg | |
| Example 3 | 1:1.9 | 230 |
| Example 4 | 1:2.0 | 250 |
| Example 5 | 1:2.1 | 280 |
| Example 6 | 1:2.2 | 300 |
Note that: the mass ratio of p-aminophenol to acetic acid refers to the addition ratio of p-aminophenol to acetic acid in step (1), and the mass of acetic acid fed to the deep acylation vessel in step (4).
Example 7
This example provides a process for producing acetaminophen.
(1) 1000kg of p-aminophenol and acetic acid (96%) are put into a dissolution kettle according to a mass ratio of 1:1.8, stirred and dissolved at 72 ℃;
(2) The dissolved material enters a primary acylation kettle through a conveying pipeline, the acylation temperature is controlled at 108 ℃, water generated by the reaction azeotropes with acetic acid, the azeotrope enters a rectifying tower for rectification, the concentration of the rectified acetic acid is more than or equal to 96%, and the rectified acetic acid is stored in an acetic acid storage tank;
(3) When the acylation rate of the first acylation reaction reaches more than 80%, feeding the material into a medium-grade acylation kettle for a second-step acylation reaction, wherein the reaction temperature is 112 ℃, and an azeotrope formed by water and acetic acid generated by the reaction enters the first-step acylation kettle through a second connecting device to participate in the first-step acylation reaction;
(4) And discharging when the acylation rate of the second acylation reaction reaches more than 95%, so as to obtain the acetaminophen.
Comparative examples 1 to 2
This comparative example provides a process for producing acetaminophen.
The difference from example 2 is that in this example, the reaction temperatures of steps (2) - (4) are 108 ℃ (comparative example 1), 118 ℃ (comparative example 2).
Comparative example 3
This comparative example provides a method of producing acetaminophen of the current state of the art.
(1) 1000kg of p-aminophenol and acetic acid are put into an acylation kettle according to the mass ratio of 1:2.5, stirring is started, and the mixture is heated to reflux;
(2) The reflux reaction is kept, the acid water azeotrope is distilled from the beginning when the acylation rate reaches more than 85%, the segmented distillation is adopted, a large amount of dilute acid collected in the early stage can be continuously used after dehydration treatment (a large amount of energy is needed to be consumed in addition), and a small amount of concentrated acid collected in the later stage can be directly fed;
(3) Discharging after the distillation of the acid-water mixture is finished, and obtaining the acetaminophen.
Performance testing
Acetaminophen was prepared using the methods provided in examples 2-7 and comparative examples 1-3, and the acylation rate, product yield, and product purity of the starting materials were calculated, with the results shown in table 2:
TABLE 2
Note that: the acylation rate refers to the acylation rate of p-aminophenol.
According to the embodiment and the performance test, the method provided by the invention can improve the conversion rate of raw materials, further improve the yield of the product and ensure that the product has higher purity.
As is clear from the comparison of examples and comparative examples, the present invention requires a stepwise acylation reaction, and the reaction temperature in the latter step is higher than that in the former step, so that the final product yield and purity are both high.
While the invention has been described in detail in the foregoing general description, embodiments and experiments, it will be apparent to those skilled in the art that modifications and improvements can be made thereto. Accordingly, such modifications or improvements may be made without departing from the spirit of the invention and are intended to be within the scope of the invention as claimed.
Claims (6)
1. A process for the preparation of acetaminophen, comprising: carrying out multi-step acylation reaction on the paracetamol and acetic acid to obtain the paracetamol;
wherein the temperature of the acylation reaction is 105-120 ℃, and the temperature of the acylation reaction in the next step is 1-10 ℃ higher than the temperature of the acylation reaction in the previous step;
in the first step of acylation reaction, an azeotrope formed by acetic acid and water is discharged out of the reaction system and does not flow back into the reaction system; during the first step of acylation reaction, part of acetic acid is added, and the mass of the added acetic acid is 20-30% of that of the para-aminophenol; and/or, during the second step of acylation reaction, adding part of acetic acid, wherein the added acetic acid accounts for 20-30% of the mass of the para-aminophenol; and/or, in the third step of acylation reaction, part of acetic acid is added, wherein the added acetic acid accounts for 20-30% of the mass of the para-aminophenol.
2. The preparation method according to claim 1, wherein the acylation reaction is a three-step acylation reaction, the first step acylation reaction temperature is 105-110 ℃, the second step acylation reaction temperature is 110-115 ℃, and the third step acylation reaction temperature is 115-120 ℃.
3. The preparation method according to claim 2, wherein the acylation ratio of the first step is 80% or more, the second step is performed, the acylation ratio of the second step is 95% or more, and the third step is performed.
4. The preparation method according to claim 1, wherein the mass ratio of the para-aminophenol to the acetic acid is 1 (1.8-2.2);
and/or the preparation method further comprises post-treatment of the crude acetaminophen product by means of recrystallization.
5. A method for continuously producing acetaminophen using an apparatus for continuously producing acetaminophen, the method comprising:
mixing p-aminophenol and acetic acid, sending the mixture into a primary acylation kettle to carry out a first acylation reaction, sending the mixture into a medium-grade acylation kettle to carry out a second acylation reaction after the acylation rate reaches more than 80%, sending the mixture into a deep acylation kettle to carry out a third acylation reaction after the acylation rate reaches more than 95%, and discharging the mixture after the acylation rate reaches 99.5% to obtain the p-acetaminophen;
the temperature in the acylation kettle is 105-120 ℃, and the temperature in the subsequent acylation kettle is 1-10 ℃ higher than the temperature in the previous acylation kettle;
the device comprises a primary acylation kettle, a medium-grade acylation kettle and a deep acylation kettle which are sequentially connected; the primary acylation kettle is connected with the rectifying tower;
the device also comprises a dissolution kettle, wherein the dissolution kettle is connected with the primary acylation kettle; the temperature of the dissolution kettle is 70-90 ℃;
the device also comprises a second connecting device for connecting the primary acylation kettle and the intermediate acylation kettle, wherein an azeotrope in the second step of acylation reaction process carried out by the intermediate acylation kettle enters the primary acylation kettle through the second connecting device to participate in the first step of acylation reaction;
and/or the device also comprises a third connecting device for connecting the intermediate-stage acylation kettle and the deep acylation kettle, wherein an azeotrope in the process of the third-step acylation reaction carried out by the deep acylation kettle enters the intermediate-stage acylation kettle through the third connecting device to participate in the second-step acylation reaction;
and/or the device also comprises a fourth connecting device connected with the deep acylation kettle, and acetic acid which is needed to be added in the third step of acylation reaction is added through the fourth connecting device.
6. The method according to claim 5, characterized in that it comprises in particular:
(1) Adding the para-aminophenol and acetic acid into a dissolving kettle according to the mass ratio of (1.8-2.2) to be stirred and dissolved at 70-90 ℃;
(2) The dissolved material enters a primary acylation kettle through a conveying and connecting device, a first step of acylation reaction is carried out at 105-110 ℃, water generated by the reaction and acetic acid form an azeotrope, and a rectifying tower is used for recycling;
(3) When the acylation rate of the first acylation reaction reaches more than 80%, feeding the material into a medium-grade acylation kettle for a second-step acylation reaction, wherein the reaction temperature is 110-115 ℃, and an azeotrope formed by water and acetic acid generated by the reaction enters the first-grade acylation kettle through a second connecting device to participate in the first-step acylation reaction;
(4) When the acylation rate of the second acylation reaction reaches more than 95%, feeding the material into a deep acylation kettle, and adding part of acetic acid to perform a third step of acylation reaction, wherein the reaction temperature is 115-120 ℃, and an azeotrope formed by water generated by the reaction and the acetic acid enters a medium-grade acylation kettle through a third connecting device to participate in the second step of acylation reaction;
(5) And discharging after the acylation rate of the third acylation reaction reaches 99.5%, so as to obtain the acetaminophen.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011329494.XA CN112479914B (en) | 2020-11-24 | 2020-11-24 | Device and method for continuously producing acetaminophen |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011329494.XA CN112479914B (en) | 2020-11-24 | 2020-11-24 | Device and method for continuously producing acetaminophen |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN112479914A CN112479914A (en) | 2021-03-12 |
| CN112479914B true CN112479914B (en) | 2023-05-09 |
Family
ID=74933799
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202011329494.XA Active CN112479914B (en) | 2020-11-24 | 2020-11-24 | Device and method for continuously producing acetaminophen |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN112479914B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115872885B (en) * | 2022-11-25 | 2024-10-18 | 河北冀衡药业股份有限公司 | Preparation method of acetaminophen with controlled content of acetaminophen impurity N |
Citations (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4324911A (en) * | 1979-10-10 | 1982-04-13 | Hoechst Aktiengesellschaft | Process for the continuous preparation of diacetyl ethylene diamine |
| CN1108241A (en) * | 1993-04-30 | 1995-09-13 | 赫希斯特人造丝公司 | Improved process for preparing acyl aminophenols |
| RU2309143C1 (en) * | 2006-03-27 | 2007-10-27 | Айрат Талгатович Ситдиков | Method for production of n,n,n',n'-tetraacetylethylene diamine |
| CN101067091A (en) * | 2007-06-08 | 2007-11-07 | 清华大学 | Solid catalysis process of preparing biodiesel oil continuously with high acid value material |
| CN101654513A (en) * | 2009-09-14 | 2010-02-24 | 江苏中鲈科技发展股份有限公司 | Method and device for continuously producing poly terephthalic acid-1, 3-propylene glycol ester |
| CN101962337A (en) * | 2009-07-21 | 2011-02-02 | 通用电气医疗集团股份有限公司 | Continuous acetylize technology in non-ionic x-ray contrast agents synthetic |
| CN101981000A (en) * | 2008-03-28 | 2011-02-23 | 化工产品开发公司Seppic | Method for the continuous synthesis of an N-acylated compound, and equipment for implementing said method |
| CN103641735A (en) * | 2013-08-29 | 2014-03-19 | 蚌埠丰原医药科技发展有限公司 | Co-production method for paracetamol and butyl acetate |
| CN104672178A (en) * | 2013-12-03 | 2015-06-03 | 中国科学院大连化学物理研究所 | Continuous reaction method for catalyzing epoxidation of hydrogen peroxide oxyalkylene |
| CN105152956A (en) * | 2015-08-05 | 2015-12-16 | 安丘市鲁安药业有限责任公司 | Process and device for acylation reaction of acetaminophen |
| CN105837399A (en) * | 2016-04-29 | 2016-08-10 | 四川福思达生物技术开发有限责任公司 | Trichlorobenzene continuous production process |
| CN107556207A (en) * | 2017-10-13 | 2018-01-09 | 烟台安诺其精细化工有限公司 | A kind of synthetic method of 3-acetylaminoaniline hydrochloride |
| CN107790078A (en) * | 2017-12-08 | 2018-03-13 | 南京大学 | A kind of device and technique for producing paracetamol |
| CN107903183A (en) * | 2017-11-15 | 2018-04-13 | 福州大学 | Method of comprehensive utilization and device containing sour DMF solution |
| CN108147975A (en) * | 2017-12-28 | 2018-06-12 | 浙江迪邦化工有限公司 | A kind of continuous production method of 3-acetylaminoaniline hydrochloride |
| CN109438171A (en) * | 2018-11-27 | 2019-03-08 | 浙江三美化工股份有限公司 | A kind of method that gas phase continuously synthesizes 2,3,3,3- tetrafluoropropene |
| CN109608353A (en) * | 2019-01-15 | 2019-04-12 | 浙江迪邦化工有限公司 | A kind of continuous production technology and device of 3-acetylaminoaniline |
-
2020
- 2020-11-24 CN CN202011329494.XA patent/CN112479914B/en active Active
Patent Citations (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4324911A (en) * | 1979-10-10 | 1982-04-13 | Hoechst Aktiengesellschaft | Process for the continuous preparation of diacetyl ethylene diamine |
| CN1108241A (en) * | 1993-04-30 | 1995-09-13 | 赫希斯特人造丝公司 | Improved process for preparing acyl aminophenols |
| RU2309143C1 (en) * | 2006-03-27 | 2007-10-27 | Айрат Талгатович Ситдиков | Method for production of n,n,n',n'-tetraacetylethylene diamine |
| CN101067091A (en) * | 2007-06-08 | 2007-11-07 | 清华大学 | Solid catalysis process of preparing biodiesel oil continuously with high acid value material |
| CN101981000A (en) * | 2008-03-28 | 2011-02-23 | 化工产品开发公司Seppic | Method for the continuous synthesis of an N-acylated compound, and equipment for implementing said method |
| CN101962337A (en) * | 2009-07-21 | 2011-02-02 | 通用电气医疗集团股份有限公司 | Continuous acetylize technology in non-ionic x-ray contrast agents synthetic |
| CN101654513A (en) * | 2009-09-14 | 2010-02-24 | 江苏中鲈科技发展股份有限公司 | Method and device for continuously producing poly terephthalic acid-1, 3-propylene glycol ester |
| CN103641735A (en) * | 2013-08-29 | 2014-03-19 | 蚌埠丰原医药科技发展有限公司 | Co-production method for paracetamol and butyl acetate |
| CN104672178A (en) * | 2013-12-03 | 2015-06-03 | 中国科学院大连化学物理研究所 | Continuous reaction method for catalyzing epoxidation of hydrogen peroxide oxyalkylene |
| CN105152956A (en) * | 2015-08-05 | 2015-12-16 | 安丘市鲁安药业有限责任公司 | Process and device for acylation reaction of acetaminophen |
| CN105837399A (en) * | 2016-04-29 | 2016-08-10 | 四川福思达生物技术开发有限责任公司 | Trichlorobenzene continuous production process |
| CN107556207A (en) * | 2017-10-13 | 2018-01-09 | 烟台安诺其精细化工有限公司 | A kind of synthetic method of 3-acetylaminoaniline hydrochloride |
| CN107903183A (en) * | 2017-11-15 | 2018-04-13 | 福州大学 | Method of comprehensive utilization and device containing sour DMF solution |
| CN107790078A (en) * | 2017-12-08 | 2018-03-13 | 南京大学 | A kind of device and technique for producing paracetamol |
| CN108147975A (en) * | 2017-12-28 | 2018-06-12 | 浙江迪邦化工有限公司 | A kind of continuous production method of 3-acetylaminoaniline hydrochloride |
| CN109438171A (en) * | 2018-11-27 | 2019-03-08 | 浙江三美化工股份有限公司 | A kind of method that gas phase continuously synthesizes 2,3,3,3- tetrafluoropropene |
| CN109608353A (en) * | 2019-01-15 | 2019-04-12 | 浙江迪邦化工有限公司 | A kind of continuous production technology and device of 3-acetylaminoaniline |
Also Published As
| Publication number | Publication date |
|---|---|
| CN112479914A (en) | 2021-03-12 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104788345B (en) | A kind of production method of high-purity hydrochloric acid metformin | |
| CN105601542B (en) | Method for crystallizing N-carbamylglutamic acid by using mixed acid | |
| CN112479914B (en) | Device and method for continuously producing acetaminophen | |
| CN108129267B (en) | Low-temperature full-continuous reaction system and application | |
| CN103803584B (en) | Ammonium bifluoride preparation method | |
| CN104311448A (en) | Preparation method of dinitolmide | |
| CN104710375B (en) | Method for producing THEIC | |
| CN107652180A (en) | The production method of tributyrin | |
| CN111087326A (en) | Method for refining guanidine nitrate | |
| CN105294797A (en) | Preparation method for methyltestosterone | |
| CN108164416B (en) | Novel process for preparing monomethyl azelate based on biodiesel | |
| CN103420863A (en) | Mefenamic acid short-process synthesis preparation and refining method | |
| CN106316921B (en) | A kind of preparation method of acemetacin | |
| CN103694137A (en) | Production method of 2-fluorine-4-nitrobenzonitrile | |
| CN109232508B (en) | Preparation method of 1, 1-cyclohexyl diacetic anhydride | |
| CN106518704A (en) | Preparation method of salicylamide | |
| CN108085133B (en) | Efficient separation and extraction method of solid goose oil and liquid goose oil | |
| CN115894292B (en) | Preparation method of L-caprolaconitrile | |
| CN115160121B (en) | Continuous production process for preparing azelaic acid based on monomethyl azelate | |
| CN118388558B (en) | Anhydrous psicose crystal and preparation method thereof | |
| CN116410130A (en) | Crystallization and purification process of 2-cyanopyridine | |
| CN105732473A (en) | Preparation method of novel catalyzed and synthesized benzpyrole-2-formic acid | |
| CN108047159A (en) | A kind of production technology of L- thiazolidines -4- carboxvlate hvdrochlorides | |
| CN115819245A (en) | Novel coupling process method for rectification and melt crystallization of mononitrotoluene | |
| CN106699563A (en) | Production technology of tert-butyl pyrocarbonate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |