CN114085135A - Continuous production method suitable for ibuprofen Friedel-crafts reaction - Google Patents
Continuous production method suitable for ibuprofen Friedel-crafts reaction Download PDFInfo
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- CN114085135A CN114085135A CN202111286033.3A CN202111286033A CN114085135A CN 114085135 A CN114085135 A CN 114085135A CN 202111286033 A CN202111286033 A CN 202111286033A CN 114085135 A CN114085135 A CN 114085135A
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- 238000005727 Friedel-Crafts reaction Methods 0.000 title claims abstract description 82
- 238000000034 method Methods 0.000 title claims abstract description 48
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 title claims abstract description 36
- 229960001680 ibuprofen Drugs 0.000 title claims abstract description 36
- 238000010924 continuous production Methods 0.000 title claims abstract description 29
- 239000007788 liquid Substances 0.000 claims abstract description 52
- KXUHSQYYJYAXGZ-UHFFFAOYSA-N isobutylbenzene Chemical compound CC(C)CC1=CC=CC=C1 KXUHSQYYJYAXGZ-UHFFFAOYSA-N 0.000 claims abstract description 27
- 238000006243 chemical reaction Methods 0.000 claims abstract description 24
- INUNLMUAPJVRME-UHFFFAOYSA-N 3-chloropropanoyl chloride Chemical compound ClCCC(Cl)=O INUNLMUAPJVRME-UHFFFAOYSA-N 0.000 claims abstract description 19
- 230000003068 static effect Effects 0.000 claims abstract description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims description 19
- 239000000463 material Substances 0.000 claims description 10
- 238000002347 injection Methods 0.000 claims description 9
- 239000007924 injection Substances 0.000 claims description 9
- 239000000243 solution Substances 0.000 claims description 9
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 7
- 239000006227 byproduct Substances 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 8
- 230000014759 maintenance of location Effects 0.000 abstract description 5
- 239000012535 impurity Substances 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 238000007599 discharging Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 239000003507 refrigerant Substances 0.000 description 2
- 230000000202 analgesic effect Effects 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 239000002221 antipyretic Substances 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 230000000536 complexating effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- -1 hydrolysis reaction Chemical compound 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
- C07C45/46—Friedel-Crafts reactions
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- 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 continuous production method suitable for Friedel-crafts reaction of ibuprofen, chloropropionyl chloride complex liquid and Friedel-crafts reaction circulating liquid are uniformly mixed in a static mixer to obtain mixed liquid and isobutylbenzene which simultaneously enter a jet reactor, wherein the mixed liquid is used as the driving flow of the jet reactor, the isobutylbenzene is used as the driven flow of the jet reactor, and chlorone solution generated by the Friedel-crafts reaction is continuously discharged through a circulating pump; the invention realizes the continuous production of ibuprofen Friedel-crafts reaction, is easy to realize automatic control, improves the safety of a system, reduces the labor intensity, shortens the reaction retention time and improves the production efficiency by more than 5-10 times.
Description
Technical Field
The invention relates to the field of chemical pharmacy, in particular to a continuous production method of ibuprofen Friedel-crafts reaction.
Background
Ibuprofen is a non-steroidal antipyretic, analgesic and anti-inflammatory drug, and the synthesis process of the ibuprofen is mainly divided into a chlorone process, a ketal process, a rearrangement and hydrolysis process and the like. The chloroketone process is the most important ring in the synthesis chain as the first step reaction of the synthesis chain, the most important point of the chloroketone process is the Friedel-crafts reaction process, and the control of the Friedel-crafts reaction is the key point for ensuring the quality of the ibuprofen product.
At present, few research or report documents on the ibuprofen Friedel-crafts reaction are provided in China, and the specific operating parameters are relatively few. In the prior art, the ibuprofen Friedel-crafts reaction is produced in an intermittent mode, namely, complex liquid generated by chloropropionyl chloride, solvent dichloromethane and catalyst aluminum trichloride is firstly added into a stirring reaction kettle with a jacket, then isobutylbenzene is dropwise added into the reaction kettle to carry out the Friedel-crafts reaction to generate chlorone and HCl and release heat in a large quantity, and the reaction temperature is adjusted by controlling the amount of frozen brine in the jacket. In the traditional technology, an intermittent mode is adopted, so that the manual operation steps are more, the reaction temperature is not stably controlled, the quality fluctuation of each batch of products is large, the production efficiency is low, and a production period is about 5-8 hours; meanwhile, in the traditional intermittent production method, rapid mixing cannot be realized by stirring in a reaction kettle, so that the selectivity of the isobutylbenzene reaction is poor, the content of generated impurity o-chloroketone is more than 3%, and the yield and quality of the product are influenced; when the production load is large, a large amount of reaction heat cannot be timely and effectively removed by controlling the jacket refrigerant of the reaction kettle to adjust the reaction temperature, so that the reaction temperature is easy to exceed the process requirement, and the product quality is influenced.
Chinese patent CN102516062A discloses a hydrolysis external circulation heat exchange process and device of friedel-crafts reaction liquid for ibuprofen synthesis, which only relates to the subsequent treatment process of the friedel-crafts reaction of ibuprofen, namely hydrolysis reaction, and is irrelevant to the friedel-crafts reaction process.
Disclosure of Invention
The invention provides a continuous production method suitable for ibuprofen Friedel-crafts reaction, which comprises the following steps:
chloropropionyl chloride complex liquid prepared from chloropropionyl chloride, dichloromethane and aluminum trichloride is uniformly mixed with Friedel-crafts reaction circulating liquid in a static mixer to obtain mixed liquid; the mixed liquid and the isobutylbenzene enter a jet reactor simultaneously for mixing and reacting, the jet reactor is connected with the top of a Friedel-crafts reaction kettle, the discharge of the jet reactor enters the Friedel-crafts reaction kettle, an outlet at the bottom of the Friedel-crafts reaction kettle is connected with a circulating pump, a chloroketone solution generated by the Friedel-crafts reaction is discharged through the circulating pump, one feed liquid enters a static mixer after being cooled by a circulating cooler and is mixed with chloropropionyl chloride complex liquid as a circulating liquid, and the other feed liquid is discharged and sent to a subsequent treatment process of chloroketone; the by-product generated by the Friedel-crafts reaction is discharged from the top of the Friedel-crafts reaction kettle and condensed and cooled by a condenser, the non-condensable gas is sent to a tail gas treatment system, and the cooled solvent returns to the Friedel-crafts reaction kettle.
The continuous production method suitable for the friedel-crafts reaction of the ibuprofen is characterized in that the friedel-crafts reaction process of the ibuprofen is a continuous production process, chloropropionyl chloride complex liquid and isobutylbenzene continuously enter a jet reactor, and chlorone solution generated by the friedel-crafts reaction is continuously discharged through a circulating pump.
The continuous production method suitable for the Friedel-crafts reaction of ibuprofen is characterized in that chloropropionyl chloride complex liquid and Friedel-crafts reaction circulating liquid are uniformly mixed in a static mixer to obtain mixed liquid and isobutylbenzene which simultaneously enter a jet reactor, wherein the mixed liquid is used as the driving flow of the jet reactor, and the isobutylbenzene is used as the driven flow of the jet reactor.
The continuous production method suitable for the Friedel-crafts reaction of ibuprofen is characterized in that the mass ratio of the mixed liquid and the isobutylbenzene 10 in the injection reactor is 10-100: 1.
The continuous production method suitable for the Friedel-crafts reaction of ibuprofen is characterized in that the feeding mass ratio of mixed liquid and isobutylbenzene in a jet reactor is 20-60: 1.
The continuous production method suitable for the Friedel-crafts reaction of ibuprofen is characterized in that the reaction temperature in a Friedel-crafts reaction kettle is 0-15 ℃; the temperature of the outlet of the circulating cooler is controlled to be-10-5 ℃.
The continuous production method suitable for the Friedel-crafts reaction of ibuprofen is characterized in that the reaction temperature in a Friedel-crafts reaction kettle is 5-10 ℃, and the outlet temperature of a circulating cooler is controlled at-5-0 ℃; .
The continuous production method suitable for the Friedel-crafts reaction of ibuprofen is characterized in that the retention time of materials in a Friedel-crafts reaction kettle is 0.2-1.5 hours.
The continuous production method suitable for the Friedel-crafts reaction of ibuprofen is characterized in that the retention time of materials in a Friedel-crafts reaction kettle is 0.5-1 hour.
The invention aims to overcome the defects in the prior art, provides a production method suitable for ibuprofen Friedel-crafts reaction continuity, improves the production efficiency, reduces the generation amount of impurity o-chloroketone, and improves the product quality.
Compared with the prior art, the invention has the following advantages:
(1) the method has the advantages of realizing continuous production of ibuprofen Friedel-crafts reaction, easily realizing automatic control, improving the safety of a system, reducing labor intensity, shortening reaction retention time and improving production efficiency by more than 5-10 times.
(2) The static mixer and the jet reactor are adopted in the process, so that the reaction materials can be fully mixed, the selectivity of the isobutylbenzene is improved, the content of the byproduct impurity, namely the o-chloroketone, is reduced to be below 2.0 percent, and the product yield is improved.
(3) The regulation of the Friedel-crafts reaction temperature can be accurately controlled by selecting a proper circulation ratio, the outlet temperature of a circulation cooler and the jacket refrigerant flow of the Friedel-crafts reaction kettle, and the accurate control of the temperature can ensure that the Friedel-crafts reaction is more stable, thereby ensuring the stability of the product quality.
Drawings
FIG. 1 is a schematic flow chart of a continuous production method suitable for Friedel-crafts reaction of ibuprofen disclosed by the invention, wherein 1, a static mixer is arranged; 2. a spray reactor; 3. a Friedel-crafts reaction kettle; 4. a circulation pump; 5. a circulation cooler; 6. a condenser; 7. a tail gas treatment system; 8. a subsequent treatment process of the chloroketone; 9. chloropropionyl chloride complex liquid; 10. isobutylbenzene.
Detailed Description
The technical solution in the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings of the present invention.
The invention provides a continuous production method suitable for ibuprofen Friedel-crafts reaction, which adopts the process flow and equipment shown in figure 1, and the specific embodiment is as follows:
example 1
Chloropropionyl chloride complex liquid 9 prepared from chloropropionyl chloride, dichloromethane and aluminum trichloride with the flow of 367.1kg/h is uniformly mixed with Friedel-crafts reaction circulating liquid in a static mixer 1 to obtain mixed liquid; simultaneously feeding mixed liquor and 111.2kg/h of isobutylbenzene 10 into the jet reactor 2 for reaction, wherein the mixed liquor is used as a driving flow of the jet reactor 2, and the isobutylbenzene 10 is used as a driven flow of the jet reactor 2; the injection reactor 2 is connected with the top of a Friedel-crafts reaction kettle 3 with stirring, the materials enter the Friedel-crafts reaction kettle 3 for further reaction, and the reaction temperature in the kettle is controlled to be 5 ℃; discharging the chloroketone solution through a circulating pump 4, wherein feed liquid with the flow rate of 4000kg/h is cooled to-2 ℃ through a circulating cooler 5 and then enters a static mixer 1 to be used as circulating liquid to be mixed with chloropropionyl chloride complexing liquid 9, the other feed liquid with the flow rate of 444.5kg/h is sent to a subsequent chloroketone treatment process 8 through the circulating pump 4, and the material liquid level of a Friedel-crafts reactor 3 is controlled to ensure that the retention time is 1 hour; the chloroketone solution containing chloroketone, dichloromethane, aluminum trichloride and a small amount of impurities and a byproduct HCl gas are generated in the jet reactor 2 and the Friedel-crafts reactor 3, wherein the mass fraction of the chloroketone is 41.07%, and the mass percentage of the impurity in the chloroketone, namely the o-chloroketone, is 1.04%.
Example 2
This example relates to a continuous process for the friedel-crafts reaction of ibuprofen. Chloropropionyl chloride complex liquid 9 prepared from chloropropionyl chloride, dichloromethane and aluminum trichloride with the flow of 367.1kg/h is uniformly mixed with Friedel-crafts reaction circulating liquid in a static mixer 1 to obtain mixed liquid; simultaneously feeding mixed liquor and 111.2kg/h of isobutylbenzene 10 into the jet reactor 2 for reaction, wherein the mixed liquor is used as a driving flow of the jet reactor 2, and the isobutylbenzene 10 is used as a driven flow of the jet reactor 2; the injection reactor 2 is connected with the top of a Friedel-crafts reaction kettle 3 with stirring, the materials enter the Friedel-crafts reaction kettle 3 for further reaction, and the reaction temperature in the kettle is controlled to be 10 ℃; discharging the chloroketone solution through a circulating pump 4, wherein feed liquid with the flow rate of 2000kg/h is cooled to 0 ℃ through a circulating material cooler 5 and then enters a static mixer 1 to be used as circulating liquid to be mixed with chloropropionyl chloride complex liquid 9, the other feed liquid with the flow rate of 441.7kg/h is sent to a subsequent chloroketone treatment process 8 through the circulating pump 4, and the liquid level of a Friedel-crafts reactor 3 is controlled to ensure that the material stays for 0.5 hour; the mixture reacts in a jet reactor 2 and a Friedel-crafts reactor 3 to generate a chloroketone solution containing chloroketone, dichloromethane, aluminum trichloride and a small amount of impurities and a byproduct HCl gas, wherein the mass fraction of the chloroketone is 40.73 percent, and the mass percentage of the impurity in the chloroketone, namely the o-chloroketone, is 1.38 percent.
Claims (9)
1. A continuous production method suitable for ibuprofen Friedel-crafts reaction is characterized by comprising the following steps:
chloropropionyl chloride complex liquid (9) prepared from chloropropionyl chloride, dichloromethane and aluminum trichloride is uniformly mixed with Friedel-crafts reaction circulating liquid in a static mixer (1) to obtain mixed liquid; the mixed liquid and isobutylbenzene (10) enter a jet reactor (2) simultaneously to be mixed and react, the jet reactor (2) is connected with the top of a Friedel-crafts reaction kettle (3), the discharge of the jet reactor (2) enters the Friedel-crafts reaction kettle (3), the outlet at the bottom of the Friedel-crafts reaction kettle (3) is connected with a circulating pump (4), a chloroketone solution generated by the Friedel-crafts reaction is discharged through the circulating pump (4), one feed liquid is cooled by a circulating cooler (5) and then enters a static mixer (1) to be mixed with chloropropionyl chloride complex liquid (9) as a circulating liquid, and the other feed liquid is discharged and sent to a chloroketone post-treatment process (8); the by-product generated by the Friedel-crafts reaction is discharged from the top of the Friedel-crafts reaction kettle (3) and condensed and cooled by a condenser (6), the non-condensable gas is sent to a tail gas treatment system (7), and the cooled solvent returns to the Friedel-crafts reaction kettle (3).
2. The continuous production method suitable for the friedel-crafts reaction of ibuprofen according to claim 1, characterized in that the friedel-crafts reaction process is a continuous production process, the chloropropionyl chloride complex liquid (9) and isobutylbenzene (10) continuously enter the injection reactor (2), and the chlorone solution generated by the friedel-crafts reaction is continuously discharged through the circulating pump (4).
3. The continuous production method suitable for the friedel-crafts reaction of ibuprofen according to claim 1, characterized in that the chloropropionyl chloride complex liquid (9) and the friedel-crafts reaction circulating liquid are uniformly mixed in the static mixer (1) to obtain a mixed liquid and isobutylbenzene (10) which simultaneously enter the injection reactor (2), wherein the mixed liquid is used as the active flow of the injection reactor (2), and the isobutylbenzene (10) is used as the passive flow of the injection reactor (2).
4. The continuous production method for ibuprofen Friedel-crafts reaction according to claim 1, characterized in that the mass ratio of the mixed liquid and the isobutylbenzene (10) in the injection reactor (2) is 10-100: 1.
5. The continuous production method suitable for the friedel-crafts reaction of ibuprofen according to claim 1, characterized in that the mass ratio of the mixed liquid in the injection reactor (2) to the feed of isobutylbenzene (10) is 20-60: 1.
6. The method for the continuous production of the friedel-crafts reaction of ibuprofen according to claim 1, characterized in that the reaction temperature in the friedel-crafts reaction kettle (3) is 0-15 ℃; the temperature of the outlet of the circulating cooler (5) is controlled to be-10 ℃ to 5 ℃.
7. The method for the continuous production method of ibuprofen Friedel-crafts reaction according to claim 1, characterized in that the reaction temperature in the Friedel-crafts reaction kettle (3) is 5-10 ℃, and the outlet temperature of the circulating cooler (5) is controlled at-5-0 ℃; .
8. The method for the continuous production of the Friedel-crafts reaction of ibuprofen according to claim 1, characterized in that the residence time of the materials in the Friedel-crafts reaction kettle (3) is 0.2 to 1.5 hours.
9. The method for the continuous production of the Friedel-crafts reaction of ibuprofen according to claim 1, characterized in that the residence time of the materials in the Friedel-crafts reaction kettle (3) is 0.5 to 1 hour.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114621066A (en) * | 2022-03-23 | 2022-06-14 | 煤炭科学技术研究院有限公司 | Method for synthesizing 2-methyl-6-propionyl naphthalene |
| CN114950331A (en) * | 2022-06-02 | 2022-08-30 | 青岛科技大学 | Continuous tubular reactor, continuous production device and Friedel-crafts reaction solvent-free continuous production method |
| CN115466170A (en) * | 2022-08-25 | 2022-12-13 | 浙江新和成股份有限公司 | Preparation method and device of ibuprofen Friedel-crafts intermediate |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114621066A (en) * | 2022-03-23 | 2022-06-14 | 煤炭科学技术研究院有限公司 | Method for synthesizing 2-methyl-6-propionyl naphthalene |
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| CN114950331A (en) * | 2022-06-02 | 2022-08-30 | 青岛科技大学 | Continuous tubular reactor, continuous production device and Friedel-crafts reaction solvent-free continuous production method |
| CN114950331B (en) * | 2022-06-02 | 2023-10-03 | 青岛科技大学 | Continuous tubular reactor, continuous production device and solvent-free continuous production method for Friedel-crafts reaction |
| CN115466170A (en) * | 2022-08-25 | 2022-12-13 | 浙江新和成股份有限公司 | Preparation method and device of ibuprofen Friedel-crafts intermediate |
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