CN115466170A - Preparation method and device of ibuprofen Friedel-crafts intermediate - Google Patents
Preparation method and device of ibuprofen Friedel-crafts intermediate Download PDFInfo
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Abstract
The invention discloses a method and a device for preparing an ibuprofen Friedel-crafts intermediate, wherein the method comprises the following steps: introducing a mixed solution containing isobutylbenzene and aluminum trichloride into a first feed port of an emulsion pump, introducing a reaction circulating liquid into a second feed port of the emulsion pump to further mix with the mixed solution, cooling acyl chloride, atomizing the acyl chloride by a spraying device, introducing the cooled acyl chloride into a third feed port of the emulsion pump, carrying out a Friedel-crafts acylation reaction on a reactant entering the emulsion pump from the three feed ports under a high-speed shearing condition, outputting the obtained reaction liquid from a discharge port, removing a byproduct, namely hydrogen chloride, cooling the hydrogen chloride, dividing the cooled reaction liquid into two feed liquids, using one feed liquid as the reaction circulating liquid to return to the second feed port of the emulsion pump, and carrying out post-treatment on the other feed liquid to obtain the ibuprofen Friedel-crafts intermediate. The preparation method improves reaction yield, reduces the content of ortho-isomer impurities, and can be carried out without adding a solvent.
Description
Technical Field
The invention relates to the field of synthesis of aryl ketone compounds, in particular to a method and a device for preparing an ibuprofen Friedel-crafts intermediate.
Background
Ibuprofen (CAS: 15687-27-1), chemical name 2-methyl-4- (2-methyl propyl) phenylacetic acid, named as "Fangwufeng", and also named as "isobenzopropionic acid", is a widely used non-steroidal anti-inflammatory drug in clinical application, and is mainly used for pain relieving and inflammation diminishing of sprain, contusion, strain, headache, lumbago, postoperative pain, etc. The medicine is recorded in national medicine dictionaries such as the United states, the British, the European Union, the Japan and the like in succession since the market, becomes one of the best-selling over-the-counter medicines all over the world, and is listed as three main products of antipyretic analgesics together with aspirin and paracetamol.
At present, the preparation method of ibuprofen mainly comprises a boot oxidation method, an aryl transposition method and a BHC method, wherein the first step of the process route is to synthesize aryl ketone compounds through Friedel-crafts reaction, wherein the boot oxidation method and the BHC method need to synthesize p-isobutylacetophenone, the aryl transposition method needs to synthesize chloroketone, and the synthesis routes of the two ketone compounds are shown as the following formula:
the first step of the three synthetic routes needs to adopt Friedel-crafts reaction to prepare intermediate ketone (called ibuprofen Friedel-crafts intermediate for short), and the batch production is mainly adopted in the current production. Firstly, acyl chloride, a solvent and a catalyst aluminum trichloride are complexed into an acylation reagent, then the acylation reagent is added into a reaction kettle, and then isobutylbenzene is dropwise added into the reaction kettle to carry out Friedel-crafts reaction. Or mixing the solvent, the isobutylbenzene and the aluminum chloride, and then dripping acyl chloride into the mixture to carry out Friedel-crafts reaction. In any way, a large amount of HCl gas is generated and a large amount of heat is released while the target product ketone is generated, the reaction temperature is usually regulated by controlling the dripping speed of isobutylbenzene or acyl chloride and the flow rate of jacket frozen brine, and on the other hand, a large amount of solvents such as dichloromethane and the like are used for diluting the reaction solution in production to reduce the heat effect, so that certain reaction selectivity and yield are obtained.
In the traditional technology, an intermittent mode is adopted, so that the manual operation steps are more, the reaction temperature is not stable to control, the quality fluctuation of each batch of products is larger, and the production efficiency is low; meanwhile, in the traditional intermittent production method, the stirring of the reaction kettle can not realize rapid mixing, and the uniform and tiny distribution of the acylation reaction liquid is difficult to control, so that the local heat release is overlarge, the selectivity of the isobutylbenzene reaction is poor, the content of the generated ortho-isomer impurities is more than 3 percent, and the yield and the 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. In addition, the use of solvents such as methylene chloride in large amounts brings about high energy consumption and serious environmental problems.
CN112882513B provides a precise temperature control device and method suitable for ibuprofen Friedel-crafts reaction. The invention adopts the tubular reaction heat exchanger and the temperature control system to realize precise temperature control, solves the problems of increased side reactions, reactor blockage and the like caused by large reaction temperature fluctuation, avoids repeated shutdown and cleaning of equipment, improves the production efficiency and the stability, has the yield of a target product of 97 percent, but has unsatisfactory reaction yield, and has the risk of separating out polymer solids and blocking pipelines under the condition of abnormal control because the tubular reactor has smaller inner diameter.
Patent CN114085135A discloses a continuous production method suitable for ibuprofen friedel-crafts reaction, which comprises the steps of complexing chloropropionyl chloride, dichloromethane and aluminum chloride to prepare chloropropionyl chloride complex liquid, then uniformly mixing the chloropropionyl chloride complex liquid with friedel-crafts reaction circulating liquid in a static mixer to obtain a mixed liquid, and simultaneously feeding the mixed liquid and isobutylbenzene into a jet reactor, wherein the mixed liquid is used as a driving flow of the jet reactor, the isobutylbenzene is used as a driven flow of the jet reactor, and a chloroketone solution generated by the friedel-crafts reaction is continuously discharged through a circulating pump, so that the continuous production of the ibuprofen friedel-crafts reaction is realized, the automatic control is easy to realize, the safety of a system is improved, the labor intensity is reduced, the reaction residence time is shortened, and the production efficiency is improved by more than 5-10 times. However, this technique still has the following problems:
(1) The complex reaction of chloropropionyl chloride, dichloromethane and aluminum chloride is a strong exothermic reaction, the adiabatic temperature rise is above 100 ℃, the complex liquid is directly mixed with Friedel-crafts reaction circulating liquid without cooling to react, the temperature of a mixing point is higher, and side reactions are increased;
(2) The chloropropionyl chloride complex liquid enters a circulating pipe and has a problem of overhigh local reaction temperature because the chloropropionyl chloride complex liquid is not subjected to liquid distribution.
(3) The chloroketone solution obtained by the reaction is discharged from the front end of the circulating cooler, namely, the isobutylbenzene and the mixed solution are discharged out of the system without entering the circulating cooler for full cooling after the reaction, so that the temperature of the reaction solution between the Friedel-crafts reaction kettle and the circulating cooler is higher, thereby causing the increase of ortho-isomer and meta-isomer, the increase of polymer impurities and the reduction of reaction yield.
(4) According to the principle of a static mixer, the chloropropionyl chloride complex liquid is difficult to be quickly and uniformly mixed by the static mixer, and the continuous steady-state operation is not facilitated.
(5) The solvent is still used in large amounts.
Disclosure of Invention
The invention provides a preparation method of an ibuprofen Friedel-crafts intermediate, which improves the reaction yield, reduces the content of ortho isomer impurities and can not add a solvent in the reaction.
The technical scheme of the invention is as follows:
a preparation method of an ibuprofen Friedel-crafts intermediate comprises the following steps:
introducing a mixed solution containing isobutylbenzene and aluminum trichloride into a first feed inlet of an emulsification pump, introducing a reaction circulating liquid into a second feed inlet of the emulsification pump to further mix the mixed solution, cooling acyl chloride, introducing the cooled acyl chloride into a third feed inlet of the emulsification pump, atomizing the acyl chloride by a spraying device, introducing the cooled acyl chloride into the emulsification pump, carrying out Friedel-crafts acylation reaction on reactants entering the emulsification pump from the three feed inlets under a high-speed shearing condition, outputting the obtained reaction liquid from a discharge outlet, removing a byproduct, namely hydrogen chloride, cooling the hydrogen chloride, dividing the cooled acyl chloride into two feed liquids, using one feed liquid as the reaction circulating liquid to return to the second feed inlet of the emulsification pump, and carrying out post-treatment on the other feed liquid to obtain the ibuprofen Friedel-crafts intermediate.
According to the invention, reaction materials are introduced into the high-speed shearing emulsification pump for reaction, the shearing rate of the emulsification pump is high, and the mass transfer efficiency and the heat transfer efficiency are effectively improved; meanwhile, acyl chloride is directly atomized by an internal spraying device and then added into an emulsification pump for reaction, so that the mass transfer efficiency and the heat transfer efficiency are further improved, and the processes of complexing and feeding are not needed. Because of the improvement of mass transfer process and heat transfer efficiency, the yield of the reaction is effectively improved, the generation of byproducts is reduced, and the reaction can be realized without adding a solvent.
Preferably, the friedel-crafts acylation reaction is carried out in a continuous manner, the reactants are continuously fed into the emulsification pump, and the reaction liquid is continuously output from the emulsification pump. The whole production process is only carried out in an emulsification pump, a pipeline, a cooler and accessory parts, and a bulky Friedel-crafts reaction kettle is not needed. The whole reaction is carried out in a continuous steady-state mode, and industrial production is facilitated.
Preferably, no solvent is added in the Friedel-crafts acylation reaction, and the traditional solvents such as dichloromethane, petroleum ether and the like are not needed to be used in the mixed solution and acyl chloride, so that the feeding volume and the post-treatment process are reduced, and the cost of the whole process is reduced.
Preferably, the ratio of the mass flow rates of the feed of the reaction circulating liquid, the mixed liquid and the acyl chloride is 7.0-46.5: 2.0-6.5: 1, preferably 11.6 to 46.5: 3.4-6.0: 1.
the feeding is carried out according to the proportion, so that the reaction can be carried out with higher efficiency. More preferably, the mass flow rate of the acyl chloride is 200-400 kg/h.
Preferably, in the mixed solution, the mass ratio of the isobutylbenzene to the aluminum chloride is from 1.
Preferably, the spraying device is a flange connection type atomizing nozzle, and the aperture of the liquid distribution hole is 0.1-1.0mm, so that acyl chloride can be dispersed into proper liquid drops.
Preferably, the reaction temperature in the emulsification pump is-25-0 ℃, preferably-20-10 ℃;
the temperature of the cooled acyl chloride is-15 to 5 ℃;
the temperature of the reaction liquid after cooling is-25 to 0 ℃, and the temperature is preferably-22 to-12 ℃.
Preferably, the emulsification pump is an in-line high-shear emulsification pump, the structure form of the emulsification pump is a fixed rotor type, the shearing rotating speed is 10000-20000rpm, and the linear speed is 28 m/s-56 m/s.
Preferably, in the emulsification pump, the second feed inlet, the first feed inlet, the third feed inlet and the discharge outlet are sequentially arranged and are consistent with the rotation direction of the emulsification pump. Or the first feeding hole, the second feeding hole, the third feeding hole and the discharging hole are arranged in sequence, and basically the same effect can be achieved.
Preferably, the residence time of the material in the emulsification pump is 10 to 25 minutes.
Preferably, the acid chloride is chloropropionyl chloride or acetyl chloride.
The invention also provides a preparation device of the ibuprofen Friedel-crafts intermediate, which comprises the following steps:
the emulsifying pump is provided with a first feeding hole, a second feeding hole, a third feeding hole and a discharging hole, and the first feeding hole is used for introducing a mixed liquid containing isobutylbenzene and aluminum trichloride;
a spraying device connected with the emulsifying pump is arranged inside the third feed port of the emulsifying pump and is used for atomizing acyl chloride;
the first cooler is connected with the third feed port;
the second cooler is communicated with the discharge hole;
and the three-way device is provided with an inlet and two outlets, the inlet of the three-way device is connected with the second cooler, and the two outlets of the three-way device are respectively connected with the second feeding hole and the product collecting device.
Preferably, in the emulsification pump, the second feed inlet, the first feed inlet, the third feed inlet and the discharge outlet are sequentially arranged and are consistent with the rotation direction of the emulsification pump.
Preferably, the emulsification pump is an in-line high-shear emulsification pump, and the structure form of the emulsification pump is a fixed rotor type.
Preferably, an emptying pipe is arranged between the emulsification pump and the second cooler and used for emptying byproduct hydrogen chloride gas, and the emptying pipe is connected with a tail gas treatment system.
Preferably, the spraying device is a flange connection type atomizing nozzle, and the aperture of the liquid distribution hole is 0.1-1.0mm
Compared with the prior art, the invention has the following advantages:
(1) The operating mode of Friedel-crafts reaction for ibuprofen production is optimized from intermittent to continuous, so that the automation control is facilitated, and the labor cost is reduced.
(2) The reaction of the invention is carried out in an emulsion pump, a pipeline and a cooler, and a bulky Friedel-crafts reaction kettle is not needed, thereby greatly saving the equipment cost.
(3) The invention realizes the solvent-free reaction, does not need to use a large amount of dichloromethane, petroleum ether and other solvents which are difficult to recover and serious in pollution, and is more energy-saving, environment-friendly and high in degree of greenness.
(4) The acyl chloride enters an emulsion pump after being atomized by a spraying device and is mixed with the mixed liquid and the reaction circulating liquid, micro liquid drops below 2 microns are generated through the high-rotating-speed violent shearing action of the emulsion pump, the micron-sized mixing reaction of the isobutylbenzene and the acylating reagent is realized, the local reaction overheating of the Friedel-crafts reaction can be effectively avoided, the reaction yield can be improved to more than 98%, and the ortho-isomer impurities are controlled to be below 1%. And the generation of micro liquid drops greatly increases the contact area and the mass transfer rate, so that the reaction rate is greatly accelerated, and the retention time can be shortened to 10-25 minutes.
Drawings
Fig. 1 is a schematic diagram of the reaction apparatus of the ibuprofen friedel-crafts intermediate of the present invention.
FIG. 2 is a gas chromatography detection spectrum of Friedel-crafts reaction solution in example 2 of the present invention.
Wherein, 1-mixed solution; 2-acyl chloride; 3-an emulsification pump; 4-a first cooler; 5-a second cooler; 6-product; 7-reaction circulating liquid; 8-emptying the pipe; a-a second feed port; b-a first feed port; c-a third feed port; d-discharging port; e-a spraying device.
Detailed Description
Fig. 1 is a schematic diagram of a reaction apparatus of the ibuprofen friedel-crafts intermediate of the present invention, and as can be seen from fig. 1, the preparation method has the following process:
(1) Mixing isobutylbenzene and aluminum trichloride into a mixed solution 1, and continuously pumping the mixed solution into a first feeding hole b of an emulsification pump 3;
(2) The method comprises the following steps that a reaction circulating liquid 7 enters an emulsification pump 3 through a second feed port a of the emulsification pump 3, a mixed liquid 1 and the reaction circulating liquid 7 are further mixed in the emulsification pump, acyl chloride 2 is cooled by a first cooler 4 and then enters a third feed port c of the emulsification pump 3, the mixture is atomized by an internally arranged spraying device e and then enters the emulsification pump 3 to be mixed with the mixed liquid 1 and the reaction circulating liquid 7 for rapid reaction, then the feed liquid is output through a discharge port d of the emulsification pump, a byproduct hydrogen chloride gas generated by Friedel-crafts reaction is firstly sent to a tail gas treatment system from an emptying pipe 8, the feed liquid without the byproduct enters a second cooler 5, one feed liquid is cooled by the second cooler 5 and then returns to the second feed port a of the emulsification pump 3 as the reaction circulating liquid 7, and the other feed liquid is discharged as a product 6 and enters a subsequent hydrolysis process; the byproduct hydrogen chloride gas generated by the Friedel-crafts reaction is sent to a tail gas treatment system from an emptying pipe 8.
Example 1:
mixing isobutylbenzene and aluminum trichloride according to the mass ratio of 1.98 to prepare a mixed solution 1, continuously pumping the mixed solution into a first feed port b of an emulsion pump 3 at the flow rate of 742.4kg/h, mixing the mixed solution with a reaction circulating solution entering the emulsion pump 3 through a second feed port a of the emulsion pump 3, and merging the mixed solution, wherein the flow rate of the mixed solution is 3324.6kg/h. After acetyl chloride 2 is cooled to-5 ℃ by a first cooler 4, the acetyl chloride enters a third feeding port c of an emulsification pump 3 at the flow rate of 221.1kg/h, is atomized by an internal spraying device e and then enters the emulsification pump 3, the rotating speed of the emulsification pump 3 is controlled to be 10000rpm, the linear speed is 28m/s, and the feed liquid in the emulsification pump 3 is sheared into tiny droplets at high speed to realize rapid dispersion, so that the problem of local reaction overheating is avoided; in addition, the generation of the tiny liquid drops greatly increases the contact area and the mass transfer rate, thereby accelerating the Friedel-crafts reaction rate. The reaction temperature in the emulsification pump 3 is-15 ℃. And then the feed liquid is discharged from a discharge port d of the emulsification pump 3 and enters a second cooler 5, the temperature of the feed liquid is controlled to be minus 17 ℃ after the feed liquid passes through the second cooler 5, one feed liquid is used as a reaction circulating liquid 7 and returns to a second feed port a of the emulsification pump 3, the flow rate of the reaction circulating liquid 7 is 2582.2kg/h, and the retention time of the feed liquid is 10 minutes. The other feed liquid as a product 6 is discharged at the flow rate of 860.7kg/h and enters a subsequent hydrolysis process; the byproduct hydrogen chloride gas generated by the Friedel-crafts reaction is sent to a tail gas treatment system from an evacuation pipe 8. The extracted product 6 contains 474.1kg of p-isobutylacetophenone, the content of isomer impurity ortho-ketone is 3.46kg, the molar yield of the product p-isobutylacetophenone is 98.4%, and the content of ortho-isomer impurity relative to the product is 0.73%.
Example 2:
isobutylbenzene and aluminum trichloride are mixed according to the mass ratio of 1:0.98 to prepare a mixed solution 1, and are continuously pumped into a first feed port b of an emulsification pump 3 at the flow rate of 1326.4kg/h, and then are mixed with a reaction circulating liquid which enters the emulsification pump 3 through a second feed port a of the emulsification pump 3, and the mixed solution is 11605.7kg/h. After acetyl chloride 2 is cooled to-5 ℃ by a first cooler 4, the acetyl chloride enters a third feeding port c of an emulsification pump 3 at the flow rate of 221.1kg/h, is atomized by an internal spraying device e and then enters the emulsification pump 3, the rotating speed of the emulsification pump 3 is controlled to be 10000rpm, the linear speed is 28m/s, and the feed liquid in the emulsification pump 3 is sheared into tiny droplets at high speed to realize rapid dispersion, so that the problem of local reaction overheating is avoided; in addition, the generation of the tiny liquid drops greatly increases the contact area and the mass transfer rate, thereby accelerating the Friedel-crafts reaction rate. The reaction temperature in the emulsification pump 3 is-15 ℃. And then the feed liquid is discharged from a discharge port d of the emulsion pump 3 and enters a second cooler 5, the temperature of the feed liquid is controlled to be-17 ℃ after passing through the second cooler 5, one feed liquid is used as a reaction circulating liquid 7 and returns to a second feed port a of the emulsion pump 3, the flow rate of the reaction circulating liquid 7 is 10279.3kg/h, and the retention time of the feed liquid is 15 minutes. Discharging the other feed liquid as a product 6 at the flow rate of 862.8kg/h, and entering a subsequent hydrolysis process; the byproduct hydrogen chloride gas generated by the Friedel-crafts reaction is sent to a tail gas treatment system from an evacuation pipe 8. The extracted product 6 contains 478.0kg of p-isobutylacetophenone, the content of isomer impurity ortho-ketone is 1.76kg, the molar yield of the product p-isobutylacetophenone is 99.2%, and the content of ortho-isomer impurity relative to the product is 0.36%.
Example 3:
isobutylbenzene and aluminum trichloride are mixed according to the mass ratio of 1.39 to prepare a mixed solution 1, the mixed solution is continuously pumped into a first feed inlet b of an emulsification pump 3 at the flow rate of 1329.6kg/h, and then mixed and merged with a reaction circulating solution which enters the emulsification pump 3 through a second feed inlet a of the emulsification pump 3, and the flow rate of the mixed solution is 3911.8kg/h after merging. After acetyl chloride 2 is cooled to-5 ℃ by a first cooler 4, the acetyl chloride enters a third feed port c of an emulsification pump 3 at the flow rate of 221.1kg/h, is atomized by an internal spraying device e and then enters the emulsification pump 3, the rotation speed of the emulsification pump 3 is controlled to 10000rpm, the linear speed is 28m/s, and the feed liquid in the emulsification pump 3 is sheared into tiny droplets at high speed to realize rapid dispersion, so that the problem of local reaction overheating is avoided; in addition, the generation of the tiny liquid drops greatly increases the contact area and the mass transfer rate, thereby accelerating the Friedel-crafts reaction rate. The reaction temperature in the emulsification pump 3 is-15 ℃. And then the feed liquid is discharged from a discharge port d of the emulsion pump 3 and enters a second cooler 5, the temperature of the feed liquid is controlled to be-17 ℃ after passing through the second cooler 5, one feed liquid is used as a reaction circulating liquid 7 and returns to a second feed port a of the emulsion pump 3, the flow of the reaction circulating liquid 7 is 2582.2kg/h, and the retention time of the feed liquid is 15 minutes. The other feed liquid is taken as a product 6 and discharged at the flow rate of 1447.9kg/h to enter a subsequent hydrolysis procedure; the byproduct hydrogen chloride gas generated by the Friedel-crafts reaction is sent to a tail gas treatment system from an evacuation pipe 8. 491.8kg of p-isobutylacetophenone is contained in the extracted product 6, the content of isomer impurity ortho-ketone is 1.52kg, the molar yield of the product p-isobutylacetophenone is 99.1%, and the content of ortho-isomer impurity relative to the product is 0.31%.
Example 4:
mixing isobutylbenzene and aluminum trichloride according to the mass ratio of 1.98 to prepare a mixed solution 1, continuously pumping the mixed solution into a first feed port b of an emulsion pump 3 at the flow rate of 742.4kg/h, mixing the mixed solution with a reaction circulating solution entering the emulsion pump 3 through a second feed port a of the emulsion pump 3, and merging the mixed solution, wherein the flow rate of the mixed solution is 3324.6kg/h. After acetyl chloride 2 is cooled to-5 ℃ by a first cooler 4, the acetyl chloride enters a third feeding port c of an emulsification pump 3 at the flow rate of 221.1kg/h, is atomized by an internal spraying device e and then enters the emulsification pump 3, the rotating speed of the emulsification pump 3 is controlled to be 10000rpm, the linear speed is 28m/s, and the feed liquid in the emulsification pump 3 is sheared into tiny droplets at high speed to realize rapid dispersion, so that the problem of local reaction overheating is avoided; in addition, the generation of the tiny liquid drops greatly increases the contact area and the mass transfer rate, thereby accelerating the Friedel-crafts reaction rate. The reaction temperature in the emulsification pump 3 is-10 ℃. And then the feed liquid is discharged from a discharge port d of the emulsion pump 3 and enters a second cooler 5, the temperature of the feed liquid is controlled to be-13 ℃ after passing through the second cooler 5, one feed liquid is used as a reaction circulating liquid 7 and returns to a second feed port a of the emulsion pump 3, the flow of the reaction circulating liquid 7 is 2582.2kg/h, and the retention time of the feed liquid is 15 minutes. The other feed liquid as a product 6 is discharged at the flow rate of 858.2kg/h and enters a subsequent hydrolysis procedure; the byproduct hydrogen chloride gas generated by the Friedel-crafts reaction is sent to a tail gas treatment system from an evacuation pipe 8. The extracted product 6 contains 472.1kg of p-isobutylacetophenone, the content of the isomer impurity ortho-ketone is 4.01kg, the molar yield of the product p-isobutylacetophenone is 98.0 percent, and the content of the ortho-isomer impurity relative to the product is 0.85 percent.
Example 5:
isobutylbenzene and aluminum trichloride are mixed according to the mass ratio of 1.98 to prepare a mixed solution 1, and are continuously pumped into a first feed inlet b of an emulsification pump 3 at the flow rate of 742.4kg/h, and are mixed with a reaction circulating liquid which enters the emulsification pump 3 through a second feed inlet a of the emulsification pump 3, and the flow rate of the mixed solution is 3324.6kg/h after the mixing. After acetyl chloride 2 is cooled to-5 ℃ by a first cooler 4, the acetyl chloride enters a third feeding port c of an emulsification pump 3 at the flow rate of 221.1kg/h, is atomized by an internal spraying device e and then enters the emulsification pump 3, the rotating speed of the emulsification pump 3 is controlled to be 10000rpm, the linear speed is 28m/s, and the feed liquid in the emulsification pump 3 is sheared into tiny droplets at high speed to realize rapid dispersion, so that the problem of local reaction overheating is avoided; in addition, the generation of the tiny liquid drops greatly increases the contact area and the mass transfer rate, thereby accelerating the Friedel-crafts reaction rate. The reaction temperature in the emulsification pump 3 is-15 ℃. And then the feed liquid is discharged from a discharge port d of the emulsion pump 3 and enters a second cooler 5, the temperature of the feed liquid is controlled to be-17 ℃ after passing through the second cooler 5, one feed liquid is used as a reaction circulating liquid 7 and returns to a second feed port a of the emulsion pump 3, the flow of the reaction circulating liquid 7 is 2582.2kg/h, and the retention time of the feed liquid is 25 minutes. The other feed liquid as a product 6 is discharged at the flow rate of 861.8kg/h and enters a subsequent hydrolysis procedure; the byproduct hydrogen chloride gas generated by the Friedel-crafts reaction is sent to a tail gas treatment system from an evacuation pipe 8. The extracted product 6 contains 475.6kg of p-isobutylacetophenone, the content of the isomer impurity ortho-ketone is 3.76kg, the molar yield of the product p-isobutylacetophenone is 98.7%, and the content of the ortho-isomer impurity relative to the product is 0.79%.
Example 6:
isobutylbenzene and aluminum trichloride are mixed according to the mass ratio of 1.98 to prepare a mixed solution 1, and are continuously pumped into a first feed inlet b of an emulsification pump 3 at the flow rate of 742.4kg/h, and are mixed with a reaction circulating liquid which enters the emulsification pump 3 through a second feed inlet a of the emulsification pump 3, and the flow rate of the mixed solution is 3324.6kg/h after the mixing. After acetyl chloride 2 is cooled to-5 ℃ by a first cooler 4, the acetyl chloride enters a third feed port c of an emulsification pump 3 at a flow rate of 357.55kg/h, is atomized by an internally arranged atomizing device e and then enters the emulsification pump 3, the rotating speed of the emulsification pump 3 is controlled to 20000rpm, the linear speed is 56m/s, and the feed liquid in the emulsification pump 3 is sheared into tiny droplets at a high speed to realize rapid dispersion, so that the problem of local reaction overheating is avoided; in addition, the generation of the tiny liquid drops greatly increases the contact area and the mass transfer rate, thereby accelerating the Friedel-crafts reaction rate. The reaction temperature in the emulsification pump 3 is-15 ℃. And then the feed liquid is discharged from a discharge port d of the emulsion pump 3 and enters a second cooler 5, the temperature of the feed liquid is controlled to be-17 ℃ after passing through the second cooler 5, one feed liquid is used as a reaction circulating liquid 7 and returns to a second feed port a of the emulsion pump 3, the flow of the reaction circulating liquid 7 is 2582.2kg/h, and the retention time of the feed liquid is 10 minutes. The other feed liquid as a product 6 is discharged at the flow rate of 863.2kg/h and enters the subsequent hydrolysis process; the byproduct hydrogen chloride gas generated by the Friedel-crafts reaction is sent to a tail gas treatment system from an evacuation pipe 8. The extracted product 6 contains 477.5kg of p-isobutylacetophenone, the content of isomer impurity ortho-ketone is 1.57kg, the molar yield of the product p-isobutylacetophenone is 99.1%, and the content of ortho-isomer impurity relative to the product is 0.33%.
Example 7:
mixing isobutylbenzene and aluminum trichloride according to the mass ratio of 1.98 to prepare a mixed solution 1, continuously pumping the mixed solution into a first feed port b of an emulsion pump 3 at the flow rate of 742.4kg/h, mixing the mixed solution with a reaction circulating solution entering the emulsion pump 3 through a second feed port a of the emulsion pump 3, and merging the mixed solution, wherein the flow rate of the mixed solution is 3734.0kg/h. Cooling 2-chloropropionyl chloride 2 to-5 ℃ by a first cooler 4, then feeding the cooled 2-chloropropionyl chloride into a third feed port c of an emulsification pump 3 at a flow rate of 357.55kg/h, atomizing the 2-chloropropionyl chloride by an internal spraying device e, feeding the atomized 2-chloropropionyl chloride into the emulsification pump 3, controlling the rotation speed of the emulsification pump 3 to 10000rpm and the linear speed to be 28m/s, and shearing the feed liquid in the emulsification pump 3 at a high speed into tiny droplets to realize rapid dispersion, thereby avoiding the problem of local reaction overheating; in addition, the generation of the tiny liquid drops greatly increases the contact area and the mass transfer rate, thereby accelerating the Friedel-crafts reaction rate. The reaction temperature in the emulsification pump 3 is-15 ℃. And then the feed liquid is discharged from a discharge port d of the emulsification pump 3 and enters a second cooler 5, the temperature of the feed liquid is controlled to be minus 17 ℃ after passing through the second cooler 5, one feed liquid is used as a reaction circulating liquid 7 and returns to a second feed port a of the emulsification pump 3, the flow rate of the reaction circulating liquid 7 is 2991.6kg/h, and the retention time of the feed liquid is 10 minutes. The other feed liquid as a product 6 is discharged at the flow rate of 997.2kg/h and enters a subsequent hydrolysis process; the byproduct hydrogen chloride gas generated by the Friedel-crafts reaction is sent to a tail gas treatment system from an evacuation pipe 8. 605.8kg of chloroketone in the extracted product 6, 4.54kg of isomer impurity ortho-ketone, 98.6 percent of molar yield of the chloroketone product and 0.75 percent of ortho-isomer impurity relative to the product.
Comparative example 1:
mixing acetyl chloride and aluminum trichloride according to the mass ratio of 0.59. Introducing isobutylbenzene into a third feed port c of the emulsification pump 3 at the flow rate of 367kg/h, atomizing by an internally arranged spraying device e, and introducing the isobutylbenzene into the emulsification pump 3, wherein the rotating speed of the emulsification pump 3 is controlled to be 10000rpm, the linear speed is controlled to be 28m/s, and the reaction temperature in the emulsification pump 3 is controlled to be-9 ℃. And then the feed liquid is discharged from a discharge port d of the emulsification pump 3 and enters a second cooler 5, the temperature of the feed liquid is controlled to be minus 17 ℃ after the feed liquid passes through the second cooler 5, one feed liquid is used as a reaction circulating liquid 7 and returns to a second feed port a of the emulsification pump 3, the flow rate of the reaction circulating liquid 7 is 2582.2kg/h, and the retention time of the feed liquid is 10 minutes. The other feed liquid is taken as a product 6 and discharged at the flow rate of 860.7kg/h to enter a subsequent hydrolysis procedure; the byproduct hydrogen chloride gas generated by the Friedel-crafts reaction is sent to a tail gas treatment system from an emptying pipe 8. The extracted product 6 contains 423.9kg of p-isobutylacetophenone, the content of isomer impurity ortho-ketone is 11.44kg, the molar yield of the product p-isobutylacetophenone is 88.0%, and the content of ortho-isomer impurity relative to the product is 2.7%.
The results of comparative example 1 show that when acetyl chloride and aluminum trichloride are complexed first and then reacted, the by-products are increased and the yield of the product is significantly reduced.
Claims (12)
1. A preparation method of an ibuprofen Friedel-crafts intermediate is characterized by comprising the following steps:
introducing a mixed solution containing isobutylbenzene and aluminum trichloride into a first feed port of an emulsion pump, introducing a reaction circulating liquid into a second feed port of the emulsion pump to further mix the mixed solution, cooling acyl chloride, introducing the cooled acyl chloride into a third feed port of the emulsion pump, atomizing the acyl chloride by a spraying device, introducing the cooled acyl chloride into the emulsion pump, carrying out Friedel-crafts acylation reaction on a reactant entering the emulsion pump from the three feed ports under a high-speed shearing condition, outputting the obtained reaction liquid from a discharge port, removing a byproduct, namely hydrogen chloride, cooling the hydrogen chloride, then dividing the hydrogen chloride into two feed liquids, taking one feed liquid as the reaction circulating liquid to return to the second feed port of the emulsion pump, and carrying out post-treatment on the other feed liquid to obtain the ibuprofen Friedel-crafts intermediate.
2. The method for preparing the ibuprofen friedel-crafts intermediate according to claim 1, wherein the friedel-crafts acylation reaction is performed in a continuous manner, reactants are continuously fed into the emulsion pump, and reaction liquid is continuously output from the emulsion pump.
3. The method for the preparation of the ibuprofen friedel-crafts intermediate according to claim 1, characterized in that no solvent is added in the friedel-crafts acylation reaction.
4. The method for preparing the ibuprofen friedel-crafts intermediate according to claim 1, characterized in that the ratio of the mass flow rates of the reaction circulating liquid, the mixed liquid and the acyl chloride is 7.0-46.5: 2.0 to 6.5:1.
5. the method for preparing the ibuprofen Friedel-crafts intermediate according to claim 1 or 4, characterized in that the mass ratio of isobutylbenzene to aluminum chloride in the mixed solution is 1.39-0.98.
6. The preparation method of the ibuprofen friedel-crafts intermediate of claim 1, wherein the spraying device is provided with a flange connection type atomizing nozzle, and the aperture of the liquid distribution hole is 0.1-1.0 mm.
7. The method for the preparation of the ibuprofen friedel-crafts intermediate according to claim 1, characterized in that the reaction temperature in the emulsion pump is-25 to 0 ℃, preferably-20 to-10 ℃;
the temperature of the cooled acyl chloride is-15 to 5 ℃;
the temperature of the reaction liquid after cooling is-25 to 0 ℃, preferably-22 to-12 ℃.
8. The method for preparing the ibuprofen friedel-crafts intermediate according to claim 1, characterized in that the emulsification pump is an in-line high-shear emulsification pump, the structure form of which is a stator-rotor type, the shear rotation speed is 10000-20000rpm, and the linear speed is 28-56 m/s.
9. The method for preparing the ibuprofen Friedel-crafts intermediate according to claim 1 or 8, wherein in the emulsification pump, the second feed port, the first feed port, the third feed port and the discharge port are sequentially arranged in sequence and are in accordance with the rotation direction of the emulsification pump.
10. The process for the preparation of the ibuprofen friedel-crafts intermediate according to claim 1, characterized in that the residence time of the material in the emulsification pump is 10-25 minutes.
11. The process for the preparation of the ibuprofen friedel-crafts intermediate according to claim 1, characterized in that the acid chloride is chloropropionyl chloride or acetyl chloride.
12. The utility model provides a preparation facilities of ibuprofen fouke midbody which characterized in that includes:
the emulsifying pump is provided with a first feeding hole, a second feeding hole, a third feeding hole and a discharging hole, and the first feeding hole is used for introducing a mixed liquid containing isobutylbenzene and aluminum trichloride;
the second feed inlet is used for introducing reaction circulating liquid;
the third feed inlet is used for introducing acyl chloride;
a spraying device is arranged inside a third feeding port of the emulsification pump and is used for atomizing acyl chloride;
the first cooler is connected with the third feed port;
the second cooler is communicated with the discharge hole;
and the inlet of the three-way device is connected with the second cooler, and the two outlets of the three-way device are respectively connected with the second feeding hole and the product collecting device.
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