CN116283546B - Method for continuously preparing 2-chloro-5-bromobenzoic acid by adopting microchannel immobilized Lewis acid catalysis - Google Patents
Method for continuously preparing 2-chloro-5-bromobenzoic acid by adopting microchannel immobilized Lewis acid catalysis Download PDFInfo
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- FGERXQWKKIVFQG-UHFFFAOYSA-N 5-bromo-2-chlorobenzoic acid Chemical compound OC(=O)C1=CC(Br)=CC=C1Cl FGERXQWKKIVFQG-UHFFFAOYSA-N 0.000 title claims abstract description 32
- 238000000034 method Methods 0.000 title claims abstract description 29
- 239000002841 Lewis acid Substances 0.000 title claims abstract description 9
- 238000007171 acid catalysis Methods 0.000 title claims abstract description 9
- 150000007517 lewis acids Chemical class 0.000 title claims abstract description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 53
- 238000006243 chemical reaction Methods 0.000 claims abstract description 44
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 18
- 238000011049 filling Methods 0.000 claims abstract description 15
- IKCLCGXPQILATA-UHFFFAOYSA-N 2-chlorobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1Cl IKCLCGXPQILATA-UHFFFAOYSA-N 0.000 claims abstract description 14
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims abstract description 14
- 239000000843 powder Substances 0.000 claims abstract description 12
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 8
- 238000011068 loading method Methods 0.000 claims abstract description 5
- 238000002156 mixing Methods 0.000 claims description 16
- 238000000926 separation method Methods 0.000 claims description 16
- 239000003153 chemical reaction reagent Substances 0.000 claims description 14
- 230000003197 catalytic effect Effects 0.000 claims description 11
- 239000012295 chemical reaction liquid Substances 0.000 claims description 11
- 239000003054 catalyst Substances 0.000 claims description 10
- 239000007788 liquid Substances 0.000 claims description 9
- 238000005893 bromination reaction Methods 0.000 claims description 8
- 239000011968 lewis acid catalyst Substances 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 7
- 238000005086 pumping Methods 0.000 claims description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- 230000031709 bromination Effects 0.000 claims description 6
- 238000000605 extraction Methods 0.000 claims description 5
- 238000000227 grinding Methods 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- 238000002425 crystallisation Methods 0.000 claims description 4
- 230000008025 crystallization Effects 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 239000012074 organic phase Substances 0.000 claims description 3
- 238000007789 sealing Methods 0.000 claims description 3
- 125000001246 bromo group Chemical group Br* 0.000 claims description 2
- 238000010791 quenching Methods 0.000 claims description 2
- 230000000171 quenching effect Effects 0.000 claims description 2
- 239000000047 product Substances 0.000 abstract description 8
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 abstract description 6
- 239000006227 byproduct Substances 0.000 abstract description 4
- 238000005112 continuous flow technique Methods 0.000 abstract 1
- 238000011020 pilot scale process Methods 0.000 abstract 1
- 238000010298 pulverizing process Methods 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 12
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 10
- 238000004519 manufacturing process Methods 0.000 description 8
- 239000002994 raw material Substances 0.000 description 7
- 239000002699 waste material Substances 0.000 description 5
- LNURMIDMOXCNEH-UHFFFAOYSA-N 3-bromo-2-chlorobenzoic acid Chemical compound OC(=O)C1=CC=CC(Br)=C1Cl LNURMIDMOXCNEH-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 238000011084 recovery Methods 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 238000004064 recycling Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- MENYRYNFSIBDQN-UHFFFAOYSA-N 5,5-dibromoimidazolidine-2,4-dione Chemical compound BrC1(Br)NC(=O)NC1=O MENYRYNFSIBDQN-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 102100020888 Sodium/glucose cotransporter 2 Human genes 0.000 description 2
- 101710103228 Sodium/glucose cotransporter 2 Proteins 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000003472 antidiabetic agent Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- -1 dibromo amino silica gel Chemical compound 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 238000003912 environmental pollution Methods 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical compound OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 229940126585 therapeutic drug Drugs 0.000 description 2
- JAVZWSOFJKYSDY-UHFFFAOYSA-N 4-bromo-2-chlorobenzoic acid Chemical compound OC(=O)C1=CC=C(Br)C=C1Cl JAVZWSOFJKYSDY-UHFFFAOYSA-N 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- JVHXJTBJCFBINQ-ADAARDCZSA-N Dapagliflozin Chemical compound C1=CC(OCC)=CC=C1CC1=CC([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)=CC=C1Cl JVHXJTBJCFBINQ-ADAARDCZSA-N 0.000 description 1
- 229940123518 Sodium/glucose cotransporter 2 inhibitor Drugs 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 229940127003 anti-diabetic drug Drugs 0.000 description 1
- 230000003178 anti-diabetic effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000009172 bursting Effects 0.000 description 1
- 239000013064 chemical raw material Substances 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 229960003834 dapagliflozin Drugs 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000004134 energy conservation Methods 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- OSHOQERNFGVVRH-UHFFFAOYSA-K iron(3+);trifluoromethanesulfonate Chemical compound [Fe+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F OSHOQERNFGVVRH-UHFFFAOYSA-K 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000007040 multi-step synthesis reaction Methods 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 238000011056 performance test Methods 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000000859 sublimation Methods 0.000 description 1
- 230000008022 sublimation Effects 0.000 description 1
- 150000003463 sulfur Chemical class 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/363—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J19/0093—Microreactors, e.g. miniaturised or microfabricated reactors
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for continuously preparing 2-chloro-5-bromobenzoic acid by adopting microchannel immobilized Lewis acid catalysis, which comprises the steps of pulverizing aluminum trichloride into powder, loading the powder into a filling column to build a microchannel reaction device, reacting a dichloromethane solution of 2-chlorobenzoic acid and a dichloromethane solution of bromine in a microreactor through the aluminum trichloride filling column, recovering effluent of dichloromethane at the lower layer through a knockout, and treating effluent of upper layer after toluene is carried out, thus obtaining the product 2-chloro-5-bromobenzoic acid. The method for preparing 2-chloro-5-bromobenzoic acid by the micro-channel immobilized Lewis acid catalysis is a continuous flow process, and the method has the advantages of low improved process cost, simplicity and convenience in operation, high safety, pilot scale potential, high heat and mass transfer efficiency, high byproduct content reduction, high conversion rate and the like.
Description
Technical Field
The invention relates to a method for preparing important synthetic raw materials of antidiabetic drugs, in particular to a method for continuously preparing 2-chloro-5-bromobenzoic acid by adopting microchannel immobilized Lewis acid catalysis.
Background
The 2-chloro-5-bromobenzoic acid is an important pharmaceutical chemical raw material and can be used for synthesizing key pharmaceutical intermediates of sodium-glucose cotransporter 2 (SGLT-2) inhibitor type diabetes therapeutic drugs, such as dapagliflozin, engagliflozin, elgliflozin, sogliflozin and the like. Meanwhile, as diabetes belongs to chronic diseases and needs long-term medication, the therapeutic drugs have larger market demands. Therefore, 2-chloro-5-bromobenzoic acid is also in great market demand as a general front-end raw material for synthesizing SGLT-2 inhibitor drugs. There is a need to develop a process for preparing 2-chloro-5-bromobenzoic acid with high selectivity that is economically safe and has a marketable potential.
At present, the report and patent for preparing 2-chloro-5-bromobenzoic acid are more, and the most economical route is to directly carry out bromination reaction through 2-chlorobenzoic acid to obtain the target product. However, the problem that side reactions are difficult to control often exists in the bromination process, and the generated unavoidable isomers such as 2-chloro-3-bromobenzoic acid, 2-chloro-4-bromobenzoic acid and the like bring complicated post-treatment operation, so that the synthesis cost is obviously increased. Meanwhile, related substances of medical intermediates are increasingly required in the medical industry. Therefore, the development of a new process for preparing high-quality 2-chloro-5-bromobenzoic acid has a great market prospect.
Chongqing Bo pharmaceutical technologies Co.Ltd discloses a method for preparing 2-chloro-5-bromobenzoic acid by using 2-chlorobenzoic acid as a raw material, wherein concentrated sulfuric acid is used as a solvent and a catalyst, and bromosuccinimide (NBS) is used as a brominating reagent. The method has poor brominated regioselectivity, the content of the byproduct 2-chloro-3-bromobenzoic acid is high, the purity of the 2-chloro-5-bromobenzoic acid is 99.2%, the yield is 80.8%, the price of a reaction brominating reagent bromosuccinimide (NBS) is high, and meanwhile, a large amount of waste acid is generated in the reaction, so that the environmental pollution is serious, and the synthesis cost is increased.
Patent CN2017112395250 discloses that 2-chlorobenzoic acid is used as a raw material, sodium bromide and periodic acid are used as brominating reagents in a water and acetic acid solvent system, the yield is less than 90%, the content of byproduct 2-chloro-3-bromobenzoic acid is also larger, the selectivity of brominating area is poorer, and the periodic acid has higher safety risk in the industrialization process.
Hebei Hejia pharmaceutical technology group Co., ltd discloses a method for synthesizing 2-chloro-5-bromobenzoic acid with high selectivity, concentrated sulfuric acid and NBS are still used as a bromination system, the regional selectivity of bromination is improved through reducing sulfur salt, the ratio of the generated 2-chloro-5-bromobenzoic acid to 2-chloro-3-bromobenzoic acid is about 4:1, organic solvent extraction is used for post-treatment, mixed solvent recrystallization is used, the cost is increased, the yield is lower, and the discharge amount of waste salt in the process is large.
2-Chlorobenzoic acid is used as a raw material, halogenated hydrocarbon is used as a solvent system, ferric triflate is used as a catalyst, dibromo amino silica gel is used as a brominating reagent, and the 2-chloro-5-bromobenzoic acid is prepared. In the new method, dibromo amino silica gel can be recycled, and the recovery rate of 6 times reaches 98 percent. The process is environment-friendly, simple and convenient to operate, low in EHS risk, high in product yield (more than or equal to 95 percent) and good in quality (more than or equal to 99.8 percent), is suitable for industrial production, greatly reduces the production cost of the 2-chloro-5-bromobenzoic acid, and obviously reduces the environmental pollution and the resource consumption in the production process.
Compared with the prior art, the preparation methods of the 2-chloro-5-bromobenzoic acid disclosed by the patent CN2019104692080, the patent CN201910983073X and the patent CN Wu Gan (Suzhou) and the patent Zhejiang Meinohua pharmaceutical chemistry Co., ltd are not substantially improved, and the defects of large discharge amount of three wastes, low yield, low product purity and the like in the process are not thoroughly solved.
Disclosure of Invention
Aiming at the defects of low selectivity, more byproducts, low product purity, high discharge amount of three wastes and the like existing in the existing synthesis and preparation process of 2-chloro-5-bromobenzoic acid, the invention provides a method for continuously preparing 2-chloro-5-bromobenzoic acid by adopting microchannel immobilized Lewis acid catalysis, which is simple and convenient to operate, economic and safe, higher in yield, low in production cost, good in application prospect and has industrial amplified production value by using a micro-reaction technology.
The technical scheme is as follows: a method for continuously preparing 2-chloro-5-bromobenzoic acid by adopting microchannel immobilized Lewis acid catalysis comprises the following steps:
step (1): grinding aluminum trichloride into powder, and loading the powder into a packed column to obtain a catalytic fixed bed microchannel with a Lewis acid catalyst on the inner wall of the channel; the whole filling column channel is connected into a micro-channel reactor, so as to finish the preparation work before the reaction;
Step (2): dissolving 2-chlorobenzoic acid in an organic solvent to obtain a reaction solution A, and mixing a bromination reagent with the organic solvent to obtain a reaction solution B; and (3) simultaneously pumping the reaction liquid A and the reaction liquid B into a micro-mixer of the micro-channel reaction device, fully mixing, pumping into a catalytic fixed bed micro-channel, fully contacting, pumping into a micro-reactor of the micro-channel reaction device for reaction, and quenching and post-treating reaction effluent to obtain the catalyst.
The reaction equation of the present invention is as follows:
In the step (1), the pipe diameter of the packed column is 1-4 mm, preferably 2mm; the length of the tube is 10-20cm, preferably 15cm.
In the step (1), in a glove box at 0-25 ℃, grinding aluminum trichloride into powder, loading the powder into a filling column, introducing nitrogen into the filling column after the channel is filled with aluminum trichloride, sealing two ends and taking out the two ends to obtain a catalytic fixed bed microchannel with Lewis acid catalyst on the inner wall of the channel; and (3) the whole packed column channel is connected into a microchannel reaction device provided with a valve.
In the step (2), the organic solvent is dichloromethane; the concentration of the dichloromethane solution of the 2-chlorobenzoic acid is 1.0-2.0 mol/L, preferably 1.2-1.8 mol/L; the concentration of the methylene dichloride solution of the brominating reagent is 3.0-5.0 mol/L, preferably 4.2-5.0 mol/L; the molar ratio of the 2-chlorobenzoic acid to the brominating reagent is 1:1.0-2.0, preferably 1:1.4.
In the step (2), the brominating reagent is bromine, N-bromosuccinimide (NBS) or dibromohydantoin, preferably bromine.
In the step (2), the flow rate of the reaction liquid A is 0.10-0.40 mL/min, preferably 0.15-0.25 mL/min, and the flow rate of the reaction liquid B is 0.050-0.150 mL/min, preferably 0.060-0.126 mL/min; after fully mixing, the mixture is pumped into a catalytic fixed bed microchannel to be reserved for 4 to 8min, preferably 5min.
In the step (2), the volume of the micro-reactor is 5-50 mL, preferably 5-10 mL; the residence time of the reaction is 20 to 40min, preferably 23.8 to 26.6min; the reaction temperature in the microreactor is 20 to 40℃and preferably 30 ℃.
In the step (2), the post-treatment is to automatically separate the quenched reaction liquid in the separation device and then recover the lower dichloromethane solution, the upper effluent is poured into the separation device filled with toluene for extraction, the solution is separated after stirring for 20min, and the organic phase is obtained after cooling crystallization, filtration and drying. The volume of the pre-stored aqueous solution in the separation device is 25-38 mL, preferably 31mL; the volume of toluene in the organic extraction solution is 31-50 mL, preferably 38mL.
In the step (2), the microchannel reaction device comprises a pump A1, a pump B2, a micro-mixer, a micro-reactor and a separation device, wherein the pump A1 and the pump B2 are connected with the micro-mixer through connecting pipes in a parallel manner, and the micro-mixer, a packed column channel, the micro-reactor and the separation device are connected with each other through connecting pipes in a serial manner; and a mixing valve is arranged between the packed column channel and the microreactor.
In the step (2), the diameter of the connecting pipe is 0.5-4 mm, and the length is 10-70 cm; the diameter of the pipeline of the micro-reactor is 0.5-4 mm.
The device can be fed into a micromixer and the subsequent equipment by a precise, low-pulsation, acid-resistant and corrosion-resistant pump (such as an HPLC pump or a syringe pump), so that materials can continuously pass through the microchannel modular reaction device while the residence time of the materials is controlled. The raw material storage tank and the product collection bottle can be respectively connected at the head and the tail according to the requirements so as to realize continuous operation. The pump described in the present invention is preferably a tetrafluoro syringe pump; the model of the micromixer is T-shaped, Y-shaped or inverted Y-shaped, preferably Y-shaped; the type of the microreactor is a pipeline type reactor or a heart-shaped structure reactor, and the pipeline type reactor is preferred.
The mixing valve between the packed column channel and the microreactor may be a T-type mixing valve, a Y-type mixing valve, an inverted Y-type mixing valve or the like, preferably a Y-type mixing valve.
The diameter of the connecting pipe is 0.5-4 mm, and the connecting pipe comprises a liquid inlet pipe, a connecting pipe between a packed column channel and the microreactor and a liquid outlet pipe between the microreactor and a receiving device, wherein the length of each section of connecting pipe is 10-70 cm, preferably 10-40 cm; the diameter of the pipeline of the micro-reactor is 0.5-4 mm, preferably 0.5-2 mm; although the ultra-thin pipe diameter can effectively increase the specific surface area, the ultra-thin pipe diameter can cause the problems of liquid flowing pressure rise, blockage, pipe bursting and the like, and the material connecting pipe used in the invention needs to be controlled in the preferred range.
The beneficial effects are that:
(1) The invention adopts the microchannel reaction device to continuously prepare the 2-chloro-5-bromobenzoic acid by the bromination reaction of the 2-chlorobenzoic acid and the bromine with low cost, thereby greatly simplifying the operation. Meanwhile, the recycling of the catalyst is realized, and the problems of low selectivity, low product purity and three-waste emission in the process of catalyst recovery and reaction are solved.
(2) The invention increases the contact area through the pipeline structure of the micro-channel, can play a role in dispersing and stabilizing the active center of AlCl 3, inhibit the sublimation of AlCl 3 and improve the activity and selectivity of the AlCl 3; the fluid only consumes a small part of AlCl 3 catalyst through the packed column, so that the efficiency is improved, the service life of the fluid is prolonged, and the aim of repeated use is fulfilled.
(3) The whole process has short reaction time, simple and convenient post-treatment, can simplify the complex multi-step synthesis process, realizes the simple, convenient, efficient and high-selectivity production of the antidiabetic intermediate 2-chloro-5-bromobenzoic acid, and avoids the problems of long time consumption, complex operation and the like of the traditional process.
(4) Compared with the traditional Lewis acid catalyst, the immobilized Lewis acid catalyst has the characteristics of basically retaining the original catalytic activity, milder reaction conditions and the like, and has the remarkable advantages of low corrosiveness to equipment, easiness in realizing serialization, environmental friendliness and the like, so that the immobilized Lewis acid catalyst has a very wide industrialized application prospect in the field of pharmaceutical and chemical industry.
(5) The invention has the advantages of low toxicity and pollution, low production cost, good product quality, high profit, environmental protection, energy conservation and high efficiency, and has potential of industrial amplification.
Drawings
FIG. 1 is a schematic diagram of a synthesis route of a microchannel reactor employed in the present invention.
FIG. 2 is a nuclear magnetic resonance hydrogen spectrum of 2-chloro-5-bromobenzoic acid synthesized in example 1.
FIG. 3 is a nuclear magnetic resonance carbon spectrum of 2-chloro-5-bromobenzoic acid synthesized in example 1.
Detailed Description
The invention will be better understood from the following examples.
The microchannel reaction apparatus described in the following examples, as shown in FIG. 1, comprises a pump A1, a pump B2, a micromixer, a packed column 3, a mixing valve 4, a microreactor 5, a separation device 6 and a receiving device 7. The reaction raw materials enter a filling column which is assembled in advance through a tetrafluoro injection pump, and then are mixed and flow into a microreactor. The model of the micromixer is Y-shaped. The type of the micro-reactor is a pipeline reactor.
Example 1
(1) In a glove box at 0-25 ℃, grinding aluminum trichloride into powder, and filling the powder into a filling column, wherein the pipe diameter of the filling column is 2mm, and the pipe length is 15cm. After the channel is filled with aluminum trichloride, introducing nitrogen into a filling column, sealing two ends and taking out to obtain a catalytic fixed bed microchannel with Lewis acid catalyst on the inner wall of the channel; and (3) the whole packed column channel is connected into a microchannel reactor provided with a valve, so as to finish the preparation work before the reaction.
(2) In the microchannel reactor, a methylene chloride solution (28 mL) of 2-chlorobenzoic acid (40 mmol) and a methylene chloride solution (12 mL) of bromine (56 mmol) were pumped into the micromixer from pump A1, pump B2, respectively, at a flow rate of 0.20mL/min, and pump B2 at a flow rate of 0.086mL/min. After fully mixing, the mixture enters a packed column channel for fully contacting, a mixing valve 4 is opened to enter a micro-reactor 5, the volume of the micro-reactor 5 is 7mL, and the reaction residence time is 24.5min. The reaction temperature is 30 ℃, the reaction liquid is collected in a separation device 6, the separation device 6 is a container containing 31mL of water, the recovery liquid of dichloromethane at the lower layer and the effluent liquid of 2-chloro-5-bromobenzoic acid at the upper layer are obtained after simple extraction and liquid separation washing, the effluent liquid of 2-chloro-5-bromobenzoic acid at the upper layer is poured into the separation device containing 38mL of toluene, the separation liquid is separated after stirring for 20min, an organic phase is obtained, the temperature is reduced, crystallization, filtration and drying are carried out, and the 2-chloro-5-bromobenzoic acid is obtained, the nuclear magnetic resonance hydrogen spectrum and the carbon spectrum of which are respectively shown in fig. 2 and 3, and the yield is: 99.0%.
Comparative example 1
This comparative example was performed in a round bottom flask.
To the reaction flask was added 28mL of methylene chloride, and stirring was started, 6.26g (40 mmol) of 2-chlorobenzoic acid was added, and 10.67g (80 mmol) of aluminum trichloride was added in portions. 6.71g (42 mmol) of bromine in 6mL of methylene chloride solution are slowly added dropwise to the reaction flask, after heating to 30 ℃. After the completion of the dropwise addition, the reaction was continued for 2 hours, and 2.24g (14 mmol) of bromine was dissolved in 6mL of methylene chloride solution, followed by completion of the dropwise addition and the reaction was continued for 2 hours. After the reaction is finished, the mixture is quenched by 31mL of water, dichloromethane is recovered, 31-50 mL of toluene is used for extraction, cooling to 0-5 ℃ for crystallization and filtration, and drying is carried out, so that 2-chloro-5-bromobenzoic acid is obtained, and the yield is: 80.1%.
Example 2
The operation is the same as in example 1, except that:
The brominating reagent is N-bromosuccinimide (NBS), and the yield is: 84.2%.
Example 3
The operation is the same as in example 1, except that:
The brominating reagent is dibromohydantoin, and the yield is: 86.3%.
Example 4
The operation is the same as in example 1, except that:
In the step (2), the flow rate of the pump A1 is 0.15mL/min, the flow rate of the pump B2 is 0.064mL/min, and the yield is: 92.6%.
Example 5
The operation is the same as in example 1, except that:
In the step (1), the flow rate of the pump A1 is 0.28mL/min, the flow rate of the pump B2 is 0.120mL/min, and the yield is: 97.8%.
Example 6
Catalyst recycling performance test: the catalyst of example 1 was tested for recovery of the supported aluminum trichloride catalyst and its catalytic performance was investigated for recycling. According to the ratio in example 1, a packed column supporting aluminum trichloride and 10 sets of reaction solutions were prepared, and under the same reaction conditions as in example 1, the packed column supporting aluminum trichloride was recycled 10 times, whereby the yield of 2-chloro-5-bromobenzoic acid was 83.8%.
The invention provides a method for continuously preparing 2-chloro-5-bromobenzoic acid by adopting microchannel immobilized Lewis acid catalysis, and the method and the way for realizing the technical scheme are numerous, the above description is only a preferred embodiment of the invention, and it should be pointed out that a plurality of improvements and modifications can be made by those skilled in the art without departing from the principle of the invention, and the improvements and the modifications are also considered as the protection scope of the invention. The components not explicitly described in this embodiment can be implemented by using the prior art.
Claims (4)
1. The method for continuously preparing 2-chloro-5-bromobenzoic acid by adopting micro-channel immobilized Lewis acid catalysis is characterized by comprising the following steps:
Step (1): grinding aluminum trichloride into powder, and loading the powder into a packed column to obtain a catalytic fixed bed microchannel with a Lewis acid catalyst on the inner wall of the channel; the whole filling column channel is connected into a micro-channel reaction device; the pipe diameter of the filling column is 1-4 mm, and the pipe length is 10-20 cm; the micro-channel reaction device comprises a pump A1, a pump B2, a micro-mixer, a micro-reactor and a separation device, wherein the pump A1 and the pump B2 are connected with the micro-mixer through a connecting pipe in a parallel manner, and the micro-mixer, a packed column channel, the micro-reactor and the separation device are connected with each other through the connecting pipe in a serial manner; a mixing valve is arranged between the packed column channel and the microreactor;
Step (2): dissolving 2-chlorobenzoic acid in an organic solvent to obtain a reaction solution A, and mixing a bromination reagent with the organic solvent to obtain a reaction solution B; pumping the reaction liquid A and the reaction liquid B into a micro-mixer of a micro-channel reaction device from a pump A1 and a pump B2 respectively, fully mixing, pumping into a catalytic fixed bed micro-channel, fully contacting, pumping into a micro-reactor of the micro-channel reaction device for reaction, quenching and post-treating reaction effluent liquid to obtain the catalyst;
In the step (1), in a glove box at 0-25 ℃, grinding aluminum trichloride into powder, loading the powder into a filling column, introducing nitrogen into the filling column after the channel is filled with aluminum trichloride, sealing two ends and taking out the two ends to obtain a catalytic fixed bed microchannel with Lewis acid catalyst on the inner wall of the channel; the whole filling column channel is connected into a micro-channel reaction device provided with a valve;
In the step (2), the organic solvent is dichloromethane; the concentration of the dichloromethane solution of the 2-chlorobenzoic acid is 1.0-2.0 mol/L; the concentration of the dichloromethane solution of the bromination reagent is 3.0-5.0 mol/L; the molar ratio of the 2-chlorobenzoic acid to the brominating reagent is 1:1.0-2.0;
The brominating reagent is bromine;
In the step (2), the post-treatment is to automatically separate the quenched reaction liquid in the separation device and then recover the lower dichloromethane solution, the upper effluent is poured into the separation device with toluene for extraction, the separation is carried out after the full stirring, and the organic phase is obtained after cooling crystallization, filtration and drying.
2. The method according to claim 1, wherein in the step (2), the flow rate of the reaction liquid a is 0.10-0.40 ml/min, and the flow rate of the reaction liquid B is 0.050-0.150 ml/min; and after fully mixing, pumping the mixture into a catalytic fixed bed microchannel and reserving the mixture for 4-8 min.
3. The method according to claim 1, wherein in the step (2), the volume of the microreactor is 5-50 mL, the reaction residence time is 20-40 min, and the reaction temperature is 20-40 ℃.
4. The method according to claim 1, wherein the connecting pipe has a diameter of 0.5-4 mm and a length of 10-70 cm; the diameter of the pipeline of the microreactor is 0.5-4 mm.
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| CN105418343A (en) * | 2014-09-18 | 2016-03-23 | 联化科技股份有限公司 | Method for preparing organic bromide by using micro-channel reactor |
| CN110590541A (en) * | 2019-10-16 | 2019-12-20 | 吕东 | Preparation method of 5-bromo-2-chlorobenzoic acid |
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| CN105418343A (en) * | 2014-09-18 | 2016-03-23 | 联化科技股份有限公司 | Method for preparing organic bromide by using micro-channel reactor |
| CN110590541A (en) * | 2019-10-16 | 2019-12-20 | 吕东 | Preparation method of 5-bromo-2-chlorobenzoic acid |
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