CN111961073B - Continuous synthesis method of arylboronic acid - Google Patents
Continuous synthesis method of arylboronic acid Download PDFInfo
- Publication number
- CN111961073B CN111961073B CN202010936424.4A CN202010936424A CN111961073B CN 111961073 B CN111961073 B CN 111961073B CN 202010936424 A CN202010936424 A CN 202010936424A CN 111961073 B CN111961073 B CN 111961073B
- Authority
- CN
- China
- Prior art keywords
- continuous
- reaction
- synthesis method
- arylboronic acid
- acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic System
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
-
- 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
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention provides a continuous synthesis method of aryl boric acid. The continuous synthesis method of the arylboronic acid comprises the following steps: continuously inputting aromatic halide and organic lithium reagent into a first continuous reaction device for lithiation reaction, and continuously discharging lithiation intermediate; continuously inputting the lithiated intermediate and the borate into a second continuous reaction device for carrying out boric acid reaction, and continuously discharging a product system containing aryl boric acid; sequentially carrying out continuous quenching reaction and continuous extraction on an arylboronic acid product system to obtain a first organic phase and a first aqueous phase; and extracting and separating the first organic phase to obtain the arylboronic acid. The method for continuously synthesizing the aromatic boric acid has the advantages of low cost, high yield and purity of the aromatic boric acid and the like.
Description
Technical Field
The invention relates to the field of preparation of arylboronic acid, in particular to a continuous synthesis method of arylboronic acid.
Background
Arylboronic acids are a class of organic synthetic, pharmaceutical and chemical intermediates that are relatively stable in air, insensitive to moisture, can be stored for long periods of time, and have high reactivity. The Suzuki coupling reaction of aryl boric acid and halogenated aromatic hydrocarbon has good position selectivity and stereoselectivity, various chemical functional groups are not changed in the reaction, the reaction condition is mild, the yield is high, and the method is an important way for forming C-C bonds. Arylboronic acids find very important application in organic synthesis reactions such as the formation of C-O bonds, C-N bonds, C-S bonds. In addition, in biological, material science and medical research, arylboronic acids have been widely used for saccharide sensors, enzyme inhibitors, and transport carriers for nucleosides and saccharides.
The method for synthesizing the substituted aryl boric acid mainly comprises the following steps: organolithium reagent processes, grignard reagent processes, and palladium catalyzed oxyboronation processes.
(1) Organolithium reagent process
The organolithium reagent method generally comprises the steps of firstly reacting aryl-containing halogenated compounds with alkyl lithium to prepare fluorine-containing phenyl lithium, then reacting with trialkyl borate, and hydrolyzing with dilute acid to obtain corresponding aryl boric acid. The disadvantages are numerous, such as: the obtained aryl-containing lithiated intermediate is sensitive to temperature, and generally can deteriorate at a temperature higher than-50 ℃ to generate self-coupling and other side reactions, and impurities can be generated after the reaction time is too long. When in batch production, the time for dripping the alkyl lithium is prolonged along with the increase of the feeding amount, so that impurities are easy to generate, and the large-scale production is not facilitated. And II, using aryl halide as a raw material, wherein the price is high, part of derivatives are difficult to produce, and a large number of stable and qualified suppliers are lacked, so that the method is not suitable for large-scale production. And III, a large amount of organic lithium reagent is used, so that the potential safety hazard in the batch reaction operation process is large. IV, the reaction generally requires low temperature, the mass transfer and heat transfer of batch reaction are poor, and the energy consumption is high. VI, the reaction is easy to generate isomers, the traditional post-treatment process adopts acidification recrystallization, the separation effect on the isomers is poor, the purity of the product is low, and the requirement of medical projects on single impurities cannot be met.
(2) Grignard reagent method
The Grignard reagent method firstly prepares the Grignard reagent by the reaction of the aryl-containing bromide and magnesium scraps, then reacts with alkyl borate, and obtains corresponding aryl boric acid by dilute acid hydrolysis. The preparation method is simple in operation, but the preparation of the Grignard reagent is generally carried out under the condition of heating, the heat release in the initiation process is severe, the safety risk is high, the yield of the obtained product is generally low, the product contains anhydride, and the product is easy to dehydrate to form a trimer during recrystallization.
(3) Palladium catalyzed oxyboronation process
The method is carried out in PdCl 2 (dppf) or Pd (OAc) 2 Under catalysis, aryl halide reacts with pinacol diboronate to obtain corresponding aryl borate, and then the corresponding aryl borate is hydrolyzed to obtain aryl boric acid. The method is simple to operate and high in yield, but the pinacol diboronate is expensive and is not suitable for large-scale production.
In view of the above problems, it is necessary to provide a method for producing aromatic boric acid with high yield and high purity, which is suitable for industrial production.
Disclosure of Invention
The invention mainly aims to provide a continuous synthesis method of aryl boric acid, which aims to solve the problem that the existing preparation method of the aryl boric acid can not simultaneously meet the requirements of industrial production, high yield, low purity and the like.
In order to achieve the above object, the present invention provides a continuous synthesis method of arylboronic acid, comprising: continuously inputting aromatic halide and organic lithium reagent into a first continuous reaction device for lithiation reaction, and continuously discharging lithiation intermediate; the lithiated intermediate and the borate are continuously input into a second continuous reaction device for carrying out the boration reaction, and a product system containing aryl boric acid is continuously discharged, wherein the synthetic route is as follows:
wherein R is 1 ，R 2 Is methyl, methoxy or-CF 3 X is F or Cl; sequentially carrying out continuous quenching reaction and continuous extraction on an arylboronic acid product system to obtain a first organic phase and a first aqueous phase; and extracting and separating the first organic phase to obtain the arylboronic acid.
Further, the temperature of the lithiation reaction is-70 to-50 ℃, and the retention time of the materials is 1 to 30min; the temperature of the boration reaction is-70 to-50 ℃, and the retention time of the materials is 5 to 30min.
Further, the ratio of the moles of the aromatic halide, the organolithium reagent and the borate is 1 (1.2-1.6): (1.5-2.0), and the moles of the borate is higher than the moles of the organolithium reagent.
Further, the first continuous reaction device is a plug flow reactor, and the second continuous reaction device is a continuous stirring reaction device or a plug flow reactor.
Further, the quenching agent used in the continuous quenching reaction is an inorganic quenching agent.
Further, the inorganic quenching agent is hydrochloric acid solution, ammonium chloride solution or sodium hydroxide solution.
Further, the continuous synthesis method of aryl boric acid further comprises the following steps: carrying out continuous back extraction on the first aqueous phase and the back extractant to obtain a second aqueous phase and a second organic phase; adjusting the pH of the second aqueous phase by using a pH regulator to obtain purified water; and (3) extracting and separating the first organic phase and the second organic phase to obtain the arylboronic acid.
Further, the extraction and separation process includes: continuously concentrating the first organic phase and the second organic phase in a thin film evaporation device to obtain concentrated solution; under the action of crystallization solvent, the concentrated solution is subjected to continuous crystallization process to obtain aryl boric acid.
Further, the continuous synthesis method of the arylboronic acid further comprises the following steps: the composition of the first continuous reaction device, the reaction system of the continuous quenching reaction and the composition of the first water phase are monitored on line by adopting a process tracking technology, and the feeding speed is automatically adjusted.
By applying the technical scheme of the invention, the aromatic halide with the specific structure adopted in the continuous synthesis method has the advantages of easily available raw materials, low cost and the like, so that the aromatic halide can be used as a reaction raw material to greatly reduce the synthesis cost of the aryl boric acid. Meanwhile, the continuous reaction device has fixed volume, and the organic lithium reagent participating in the reaction in unit time is limited, so that the potential safety hazard can be greatly reduced, and the continuous synthesis method has higher safety. Compared with batch reaction, the continuous reaction device adopted in the continuous synthesis method has the advantages of large specific surface area, high heat exchange efficiency, capability of utilizing resources to the maximum extent, energy consumption reduction and probability of side reaction occurrence, and can greatly improve the yield and purity of the aromatic boric acid. On the basis, the method for continuously synthesizing the aromatic boric acid has the advantages of low cost, high yield and purity of the aromatic boric acid and the like.
Drawings
The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the description serve to explain the invention. In the drawings:
fig. 1 shows a schematic flow chart of a preferred continuous synthesis method of arylboronic acid according to example 1 of the present invention.
Detailed Description
It should be noted that, in the case of no conflict, the embodiments and features in the embodiments may be combined with each other. The present invention will be described in detail with reference to examples.
As described in the background art, the existing preparation method of aromatic boric acid has the problem that the requirements of industrial production, high yield, low purity and the like cannot be met at the same time. In order to solve the technical problems, the application provides a continuous synthesis method of aryl boric acid, which comprises the following steps: continuously inputting aromatic halide and organic lithium reagent into a first continuous reaction device for lithiation reaction, and continuously discharging lithiation intermediate; the lithiated intermediate and the borate are continuously input into a second continuous reaction device for carrying out the boration reaction, and a product system containing aryl boric acid is continuously discharged, wherein the synthetic route is as follows:
wherein R is 1 ，R 2 Is methyl, methoxy or-CF 3 X is F or Cl; sequentially carrying out continuous quenching reaction and continuous extraction on an arylboronic acid product system to obtain a first organic phase and a first aqueous phase; and extracting and separating the first organic phase to obtain the arylboronic acid.
The aromatic halide with a specific structure adopted in the continuous synthesis method has the advantages of easily available raw materials, low cost and the like, so that the aromatic halide can be used as a reaction raw material to greatly reduce the synthesis cost of the aryl boric acid. Meanwhile, the continuous reaction device has fixed volume, and the organic lithium reagent participating in the reaction in unit time is limited, so that the potential safety hazard can be greatly reduced, and the continuous synthesis method has higher safety. Compared with batch reaction, the continuous reaction device adopted in the continuous synthesis method has the advantages of large specific surface area, high heat exchange efficiency, capability of utilizing resources to the maximum extent, energy consumption reduction and probability of side reaction occurrence, and can greatly improve the yield and purity of the aromatic boric acid. On the basis, the method for continuously synthesizing the aromatic boric acid has the advantages of low cost, high yield and purity of the aromatic boric acid and the like.
As aryl lithiation intermediates are sensitive to temperature, the aryl lithiation intermediates generally deteriorate at a temperature higher than-50 ℃ to generate self-coupling and other side reactions, and impurities can be generated after the reaction time is too long. In order to reduce the occurrence probability of side reaction and improve the purity of the arylboronic acid, preferably, the lithiation reaction temperature is-70 to-50 ℃ and the material residence time is 1 to 30min; the temperature of the boration reaction is-70 to-50 ℃, and the retention time of the materials is 5 to 30min. The temperature and the material residence time of the first continuous reaction device and the boration reaction are limited in the above ranges, which is beneficial to shortening the reaction time of the reaction raw materials and improving the yield of the aryl boric acid while reducing the occurrence probability of side reactions.
In order to further increase the yield of the arylboronic acid, it is preferable that the ratio of the moles of the aromatic halide, the organolithium reagent and the borate is 1 (1.2 to 1.6): (1.5 to 2.0), and the moles of the borate is higher than the moles of the organolithium reagent, such as 1:1.2:2.0, 1:1.4:1.6, 1:1.5:1.6, etc.
In the continuous synthesis reaction, the time of each stage can be precisely controlled, and impurities generated due to longer lithiation stage time are avoided, so that the purity and the yield of the arylboronic acid are improved. The lithiation and boration reactions described above may be carried out in continuous reaction apparatus commonly used in the art. In order to further increase the specific surface area of the continuous reaction device, increase the heat exchange efficiency thereof, and reduce the energy consumption, more preferably, the first continuous reaction device is a plug flow reactor, and the second continuous reaction device is a continuous stirring reaction device or a plug flow reactor.
The type of quencher can be selected by one skilled in the art depending on the pH of the reaction system. Such as an inorganic quencher, more preferably a hydrochloric acid solution, an ammonium chloride solution or a sodium hydroxide solution (all refer to aqueous solutions unless otherwise specified). In a preferred embodiment, the above synthesis method further comprises preparing the quencher in-line, and then continuously adding the quencher to the quenching apparatus to perform a continuous quenching reaction with the product system comprising the arylboronic acid.
After continuous quenching reaction, a quenching product system is obtained, and then the quenching system and an extractant are subjected to continuous extraction process to obtain a first water phase and a first organic phase. Since the first aqueous phase also contains a small amount of arylboronic acid, in order to further increase the yield of arylboronic acid, the above-mentioned continuous synthesis method preferably further comprises: carrying out continuous back extraction on the first aqueous phase and the back extractant to obtain a second aqueous phase and a second organic phase; adjusting the pH of the second aqueous phase by using a pH regulator to obtain purified water; and (3) extracting and separating the first organic phase and the second organic phase to obtain the arylboronic acid.
The extraction and separation process can be carried out by methods commonly used in the art. In a preferred embodiment, the extraction separation process includes: continuously concentrating the first organic phase and the second organic phase in a thin film evaporation device to obtain concentrated solution; under the action of crystallization solvent, the concentrated solution is subjected to continuous crystallization process to obtain aryl boric acid. Compared with other methods, the film evaporation can lead the liquid to form larger vaporization surface area, the heat is fast and uniform to spread, the influence of liquid co-pressure is avoided, the material overheating phenomenon can be better prevented, and meanwhile, the film evaporation has the advantages of low heating temperature of the extracting solution, short time, fast evaporation speed, continuous operation, shortened separation period and the like.
In a preferred embodiment, the continuous synthesis method further comprises: the composition of the first continuous reaction device, the reaction system of the continuous quenching reaction and the composition of the first water phase are monitored on line by adopting a process tracking technology, and the feeding speed is automatically adjusted. The feeding speed of each step is automatically regulated by adopting a process tracking technology, so that the feeding is more accurate, the generation of impurities is reduced, and the purity of the aryl boric acid is improved.
The present application is described in further detail below in conjunction with specific embodiments, which should not be construed as limiting the scope of the claims.
The process flow of the arylboronic acid synthesis method in the examples is shown in fig. 1.
Example 1
The method comprises the steps of preparing a raw material solution A by online dilution of para-fluoroanisole with tetrahydrofuran, preparing a solution B by online dilution of LDA (lithium diisopropylamide) tetrahydrofuran solution with tetrahydrofuran, preparing a solution C by online dilution of triethyl borate with tetrahydrofuran, and preparing a dilute hydrochloric acid solution D by online dilution of concentrated hydrochloric acid with water.
And (3) debugging the reaction equipment by using tetrahydrofuran, and cooling the first-stage PFR (first-stage plug flow reactor) and the second-stage PFR (second-stage plug flow reactor) to-70 to-60 ℃ in an external bath after the water content of the detection system is qualified, and starting to perform material beating. The solution A and the solution B are subjected to continuous lithiation reaction in a first-stage PFR (first-stage plug flow reactor) to obtain a lithiation intermediate; the lithiated intermediate thus formed is continuously fed into the second stage PFR for continuous boration with solution C. And (3) through PAT on-line monitoring, the feeding speed and the proportion of each material are adjusted in real time, wherein the molar ratio of the para-fluoroanisole to the diisopropyllithium amide to the triethyl borate is 1:1.4:1.6, the lithiation reaction time is 5min, and the boration time is 10min.
After the reaction, the reaction system is continuously quenched by the solution D in CSTRs (continuous stirring reaction device), and then extracted and separated by the methyl tertiary butyl ether serving as an extractant in a continuous extraction device to obtain a first water phase and a first organic phase. And then continuously extracting and separating the first aqueous phase by methyl tertiary butyl ether to obtain a second organic phase. Continuously inputting the first organic phase and the second organic phase into a thin film evaporator for continuous thin film concentration to obtain concentrated solution and evaporating out solvent. The distilled solvent can be recycled to the sequential extraction steps. The concentrated solution is input into a mixed suspension mixed discharge continuous crystallizer, and simultaneously n-heptane is added for continuous crystallization, and then separation is carried out to obtain the target product. And simultaneously, continuously regulating the pH value of the second water phase to 6-9 in another CSTRs, and directly transferring the second water phase to a sewage station for treatment. 2-fluoro-5-methoxy phenylboronic acid is synthesized from p-fluoroanisole, the yield is 88%, the HPLC purity is more than or equal to 99%, the single impurity is less than or equal to 0.15%, and the daily capacity is more than 200Kg.
Example 2
The method comprises the steps of preparing a raw material solution A by online dilution of p-fluorotoluene with tetrahydrofuran, preparing a solution B by online dilution of LDA (lithium diisopropylamide) tetrahydrofuran solution with tetrahydrofuran, preparing a solution C by online dilution of triethyl borate with tetrahydrofuran, and preparing a diluted hydrochloric acid solution D by online dilution of concentrated hydrochloric acid with water.
And (3) debugging the reaction equipment by using tetrahydrofuran, and cooling the first-stage PFR (first-stage plug flow reactor) and the second-stage PFR (second-stage plug flow reactor) to-70 to-60 ℃ in an external bath after the water content of the detection system is qualified, and starting to perform material beating. The solution A and the solution B are subjected to continuous lithiation reaction in a first-stage PFR (first-stage plug flow reactor) to obtain a lithiation intermediate; the resulting lithiated intermediate is passed to a second stage PFR (second stage plug flow reactor) for continuous boration with solution C. And the feeding speed and the proportion of each material are adjusted in real time through PAT on-line monitoring. Wherein, the mol ratio of the p-fluorotoluene, the lithium diisopropylamide and the triethyl borate is 1:1.4:1.6, the lithiation reaction time is 5-10 min, and the boration time is 10-30 min.
After the reaction, the reaction system is continuously quenched by a solution D in CSTRs (continuous stirring reaction devices), and then extracted and separated by methyl tertiary butyl ether as an extractant in a continuous extraction device to obtain a first water phase and a first organic phase. And then continuously extracting and separating the first aqueous phase by methyl tertiary butyl ether to obtain a second organic phase. Continuously inputting the first organic phase and the second organic phase into a thin film evaporator for continuous thin film concentration to obtain concentrated solution and evaporating out solvent. The distilled solvent can be recycled to the sequential extraction steps. The concentrated solution is input into a mixed suspension mixed discharge continuous crystallizer, and simultaneously n-heptane is added for continuous crystallization, and then separation is carried out to obtain the target product. And simultaneously, continuously regulating the pH value of the second water phase to 6-9 in another CSTRs, and directly transferring the second water phase to a sewage station for treatment. The 2-fluoro-5-methyl phenylboronic acid is synthesized from p-fluorotoluene, the yield is 83%, the HPLC purity is more than or equal to 99% and the single impurity is less than or equal to 0.15%, and the daily capacity is more than 180Kg.
Example 3
The differences from example 1 are: the molar ratio of the para-fluoroanisole to the lithium diisopropylamide to the triethyl borate is 1:1.2:2.0.
The method comprises the steps of preparing a raw material solution A by online dilution of para-fluoroanisole with tetrahydrofuran, preparing a solution B by online dilution of LDA (lithium diisopropylamide) tetrahydrofuran solution with tetrahydrofuran, preparing a solution C by online dilution of triethyl borate with tetrahydrofuran, and preparing a dilute hydrochloric acid solution D by online dilution of concentrated hydrochloric acid with water.
And (3) debugging the reaction equipment by using tetrahydrofuran, and cooling the first-stage PFR (first-stage plug flow reactor) and the second-stage PFR (second-stage plug flow reactor) to-70 to-60 ℃ in an external bath after the water content of the detection system is qualified, and starting to perform material beating. The solution A and the solution B are subjected to continuous lithiation reaction in a first-stage PFR (first-stage plug flow reactor) to obtain a lithiation intermediate; the lithiated intermediate thus formed is continuously fed into the second stage PFR for continuous boration with solution C. And (3) through PAT on-line monitoring, the feeding speed and the proportion of each material are adjusted in real time, wherein the molar ratio of the para-fluoroanisole to the diisopropyllithium amide to the triethyl borate is 1:1.2:2.0, the lithiation reaction time is 5min, and the boration time is 10min.
After the reaction, the reaction system is continuously quenched by the solution D in CSTRs (continuous stirring reaction device), and then extracted and separated by the methyl tertiary butyl ether serving as an extractant in a continuous extraction device to obtain a first water phase and a first organic phase. And then continuously extracting and separating the first aqueous phase by methyl tertiary butyl ether to obtain a second organic phase. Continuously inputting the first organic phase and the second organic phase into a thin film evaporator for continuous thin film concentration to obtain concentrated solution and evaporating out solvent. The distilled solvent can be recycled to the sequential extraction steps. The concentrated solution is input into a mixed suspension mixed discharge continuous crystallizer, and simultaneously n-heptane is added for continuous crystallization, and then separation is carried out to obtain the target product. And simultaneously, continuously regulating the pH value of the second water phase to 6-9 in another CSTRs, and directly transferring the second water phase to a sewage station for treatment. The yield of the 2-fluoro-5-methoxyphenylboronic acid is 80%, the HPLC purity is more than or equal to 99%, and the single impurity is less than or equal to 0.15%.
Example 4
The differences from example 1 are: the molar ratio of the para-fluoroanisole to the lithium diisopropylamide to the triethyl borate is 1:1.5:1.6.
The method comprises the steps of preparing a raw material solution A by online dilution of para-fluoroanisole with tetrahydrofuran, preparing a solution B by online dilution of LDA (lithium diisopropylamide) tetrahydrofuran solution with tetrahydrofuran, preparing a solution C by online dilution of triethyl borate with tetrahydrofuran, and preparing a dilute hydrochloric acid solution D by online dilution of concentrated hydrochloric acid with water.
And (3) debugging the reaction equipment by using tetrahydrofuran, and cooling the first-stage PFR (first-stage plug flow reactor) and the second-stage PFR (second-stage plug flow reactor) to-70 to-60 ℃ in an external bath after the water content of the detection system is qualified, and starting to perform material beating. The solution A and the solution B are subjected to continuous lithiation reaction in a first-stage PFR (first-stage plug flow reactor) to obtain a lithiation intermediate; the lithiated intermediate thus formed is continuously fed into the second stage PFR for continuous boration with solution C. And (3) through PAT on-line monitoring, the feeding speed and the proportion of each material are adjusted in real time, wherein the molar ratio of the para-fluoroanisole to the diisopropyllithium amide to the triethyl borate is 1:1.5:1.6, the lithiation reaction time is 5min, and the boration time is 10min.
After the reaction, the reaction system is continuously quenched by the solution D in CSTRs (continuous stirring reaction device), and then extracted and separated by the methyl tertiary butyl ether serving as an extractant in a continuous extraction device to obtain a first water phase and a first organic phase. And then continuously extracting and separating the first aqueous phase by methyl tertiary butyl ether to obtain a second organic phase. Continuously inputting the first organic phase and the second organic phase into a thin film evaporator for continuous thin film concentration to obtain concentrated solution and evaporating out solvent. The distilled solvent can be recycled to the sequential extraction steps. The concentrated solution is input into a mixed suspension mixed discharge continuous crystallizer, and simultaneously n-heptane is added for continuous crystallization, and then separation is carried out to obtain the target product. And simultaneously, continuously regulating the pH value of the second water phase to 6-9 in another CSTRs, and directly transferring the second water phase to a sewage station for treatment. The yield of the 2-fluoro-5-methoxyphenylboronic acid is 82 percent, the HPLC purity is more than or equal to 99 percent, and the single impurity is less than or equal to 0.15 percent
Example 5
The differences from example 1 are: the molar ratio of the para-fluoroanisole to the lithium diisopropylamide to the triethyl borate is 1:1.1:1.3.
The method comprises the steps of preparing a raw material solution A by online dilution of para-fluoroanisole with tetrahydrofuran, preparing a solution B by online dilution of LDA (lithium diisopropylamide) tetrahydrofuran solution with tetrahydrofuran, preparing a solution C by online dilution of triethyl borate with tetrahydrofuran, and preparing a dilute hydrochloric acid solution D by online dilution of concentrated hydrochloric acid with water.
And (3) debugging the reaction equipment by using tetrahydrofuran, and cooling the first-stage PFR (first-stage plug flow reactor) and the second-stage PFR (second-stage plug flow reactor) to-70 to-60 ℃ in an external bath after the water content of the detection system is qualified, and starting to perform material beating. The solution A and the solution B are subjected to continuous lithiation reaction in a first-stage PFR (first-stage plug flow reactor) to obtain a lithiation intermediate; the lithiated intermediate thus formed is continuously fed into the second stage PFR for continuous boration with solution C. And (3) through PAT on-line monitoring, the feeding speed and the proportion of each material are adjusted in real time, wherein the molar ratio of the para-fluoroanisole to the diisopropyllithium amide to the triethyl borate is 1:1.1:1.3, the lithiation reaction time is 5min, and the boration time is 10min.
After the reaction, the reaction system is continuously quenched by the solution D in CSTRs (continuous stirring reaction device), and then extracted and separated by the methyl tertiary butyl ether serving as an extractant in a continuous extraction device to obtain a first water phase and a first organic phase. And then continuously extracting and separating the first aqueous phase by methyl tertiary butyl ether to obtain a second organic phase. Continuously inputting the first organic phase and the second organic phase into a thin film evaporator for continuous thin film concentration to obtain concentrated solution and evaporating out solvent. The distilled solvent can be recycled to the sequential extraction steps. The concentrated solution is input into a mixed suspension mixed discharge continuous crystallizer, and simultaneously n-heptane is added for continuous crystallization, and then separation is carried out to obtain the target product. And simultaneously, continuously regulating the pH value of the second water phase to 6-9 in another CSTRs, and directly transferring the second water phase to a sewage station for treatment. The yield of the 2-fluoro-5-methoxyphenylboronic acid is 76%, the HPLC purity is more than or equal to 99%, and the single impurity is less than or equal to 0.15%.
Comparative example 1
The existing method for synthesizing 2-fluoro-5-methoxyphenylboronic acid from p-fluoroanisole comprises the steps of calculating 200kg of p-fluoroanisole and 2000L of tetrahydrofuran by a 5000L low-temperature kettle, cooling to-75 to-65 ℃ for 4-8 h, controlling Wen Dijia LDA (lithium diisopropylamide) tetrahydrofuran solution, approximately requiring 4-10 h, dropwise adding triethyl borate after heat preservation and tracking IPC is qualified, reversely quenching a reaction system into a 12500L enamel kettle prepared with hydrochloric acid solution in advance after heat preservation and IPC tracking is qualified, and quenching for approximately 5-10 h. After quenching, methyl tertiary butyl ether is added into the kettle, the mixture is stirred, kept stand and separated, and the water phase is back extracted by the methyl tertiary butyl ether. The organic phases are combined and concentrated, then n-heptane is added dropwise, the temperature is reduced for crystallization, and the product is separated. The single batch operation time required 7 days. The yield is 70%, the HPLC purity is more than or equal to 98%, and the daily productivity is reduced to 30-70 Kg.
From the above description, it can be seen that the above embodiments of the present invention achieve the following technical effects: compared with batch reaction, the first continuous reaction device has large specific surface area and high heat exchange efficiency, can maximally utilize resources, reduce energy consumption and reduce occurrence probability of side reaction, thereby improving yield and purity of aromatic boric acid. Through the full continuous process, the productivity can be greatly improved, materials and energy sources are saved, and the purity and the yield reach expectations.
It should be noted that the terms "first," "second," and the like in the description and in the claims of the present application are used for distinguishing between similar objects and not necessarily for describing a particular sequential or chronological order. It is to be understood that the terms so used are interchangeable under appropriate circumstances such that the embodiments of the application described herein are, for example, capable of operation in sequences other than those described herein.
The above description is only of the preferred embodiments of the present invention and is not intended to limit the present invention, but various modifications and variations can be made to the present invention by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (8)
1. A continuous synthesis method of aryl boric acid, which is characterized by comprising the following steps:
continuously inputting aromatic halide and organic lithium reagent into a first continuous reaction device for lithiation reaction, and continuously discharging lithiation intermediate; the organic lithium reagent is lithium diisopropylamide;
continuously inputting the lithiated intermediate and boric acid ester into a second continuous reaction device for boric acid reaction, continuously discharging a product system containing the arylboronic acid,
the aromatic halide is selected from para-fluoroanisole and the arylboronic acid is selected from 2-fluoro-5-methoxyphenylboronic acid, or the aromatic halide is selected from para-fluorotoluene and the arylboronic acid is selected from 2-fluoro-5-methylphenylboronic acid;
when the aromatic halide is selected from the para-fluoroanisole, the synthetic route is as follows:
when the aromatic halide is selected from the para-fluorotoluene, the synthetic route is as follows:
the boric acid ester is selected from triethyl borate; the molar ratio of the para-fluoroanisole, the lithium diisopropylamide and the triethyl borate is 1:1.4:1.6 or 1:1.2:2.0 or 1:1.5:1.6, and the molar ratio of the para-fluorotoluene, the lithium diisopropylamide and the triethyl borate is 1:1.4:1.6;
sequentially carrying out continuous quenching reaction and continuous extraction on the product system of the arylboronic acid to obtain a first organic phase and a first aqueous phase; a kind of electronic device with high-pressure air-conditioning system
And extracting and separating the first organic phase to obtain the arylboronic acid.
2. The continuous synthesis method of aryl boric acid according to claim 1, wherein the lithiation reaction temperature is-70 to-50 ℃, and the material residence time is 1-30 min; the temperature of the boration reaction is-70 to-50 ℃, and the retention time of the materials is 5 to 30min.
3. The continuous synthesis method of arylboronic acid according to claim 1, wherein the first continuous reaction device is a plug flow reactor and the second continuous reaction device is a continuous stirring reaction device or a plug flow reactor.
4. The continuous synthesis method of arylboronic acid according to claim 1, wherein the quencher used in the continuous quenching reaction is an inorganic quencher.
5. The continuous synthesis method of arylboronic acid according to claim 4, wherein the inorganic quencher is hydrochloric acid solution, ammonium chloride solution or sodium hydroxide solution.
6. The continuous synthesis method of arylboronic acid according to any one of claims 1 to 5, further comprising:
carrying out continuous back extraction on the first aqueous phase and a back extractant to obtain a second aqueous phase and a second organic phase;
adjusting the pH of the second aqueous phase by using a pH regulator to obtain purified water;
and carrying out the extraction and separation process on the first organic phase and the second organic phase to obtain the arylboronic acid.
7. The continuous synthesis method of arylboronic acid of claim 6, wherein the extraction and separation process comprises:
continuously concentrating the first organic phase and the second organic phase in a thin film evaporation device to obtain concentrated solution;
and under the action of a crystallization solvent, carrying out continuous crystallization on the concentrated solution to obtain the arylboronic acid.
8. The continuous synthesis method of arylboronic acid according to claim 1, further comprising: and adopting a process tracking technology to monitor the composition in the first continuous reaction device, the reaction system of the continuous quenching reaction and the composition of the first water phase on line, and automatically adjusting the feeding speed.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010936424.4A CN111961073B (en) | 2020-09-08 | 2020-09-08 | Continuous synthesis method of arylboronic acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010936424.4A CN111961073B (en) | 2020-09-08 | 2020-09-08 | Continuous synthesis method of arylboronic acid |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN111961073A CN111961073A (en) | 2020-11-20 |
| CN111961073B true CN111961073B (en) | 2023-05-02 |
Family
ID=73392636
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010936424.4A Active CN111961073B (en) | 2020-09-08 | 2020-09-08 | Continuous synthesis method of arylboronic acid |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111961073B (en) |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MY143535A (en) * | 2006-01-13 | 2011-05-31 | Dow Agrosciences Llc | 6-(poly-substituted aryl)-4-aminopicolinates and their use as herbicides |
| CN101519411B (en) * | 2008-12-30 | 2011-07-20 | 凯莱英医药化学（天津）有限公司 | Method for preparing phenylboronic acid-2-methyl formate |
| CN102190676A (en) * | 2010-03-18 | 2011-09-21 | 拜耳技术工程（上海）有限公司 | Method and apparatus for continuously producing aryl boric acid |
| CN104119367A (en) * | 2014-07-09 | 2014-10-29 | 中国科学技术大学苏州研究院 | Preparation method of aryl boric acid |
| CN109134521B (en) * | 2018-10-16 | 2021-01-22 | 凯莱英生命科学技术(天津)有限公司 | Continuous synthesis method of 2-fluorobenzene boric acid compound |
-
2020
- 2020-09-08 CN CN202010936424.4A patent/CN111961073B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN111961073A (en) | 2020-11-20 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN109134521B (en) | Continuous synthesis method of 2-fluorobenzene boric acid compound | |
| CN105348045B (en) | A kind of method of utilization continuous stream reaction synthesis Pentafluorophenol | |
| CN101792400A (en) | Synthetic method for agomelatine | |
| CN107556302A (en) | It is a kind of to prepare the net methods of Yi Palie | |
| US20220289664A1 (en) | Synthesis method of hydroxybenzylamine | |
| CN108440229A (en) | A kind of preparation method of anti-AIDS drug big human relations intermediate cyclopropyl acetylene in accordance with the law | |
| CN111961073B (en) | Continuous synthesis method of arylboronic acid | |
| CN109970580B (en) | Extraction and preparation method of R-3-aminobutanol | |
| CN110452181B (en) | Synthesis method of 2-methyl-4-amino-5-formamide methylpyrimidine | |
| CN104788340A (en) | Method for preparing n-phenylglycinenitrile | |
| CN103361388A (en) | L-cyclic alkylamino acid synthesis method and medicinal composition containing L-cyclic alkylamino acid | |
| CN107987097B (en) | The synthesis technology of 2,6- dichloropyridine -4- boric acid pinacol ester | |
| CN102993009A (en) | Preparation method of glycerin monostearate alpha crystal | |
| CN106316892A (en) | Synthetic method of sodium houttuyfonate | |
| CN114702425A (en) | Preparation method of (S) -2-amino- (S) -3- [ pyrrolidone-2' ] alanine derivative and intermediate | |
| CN104072369A (en) | Diisopropyl malonate preparation process | |
| WO1986002924A1 (en) | Process for producing aromatic hydroxycarboxylic acid | |
| CN105085190A (en) | Preparing method of 2,6-difluoro-4-bromophenol | |
| CN112430197A (en) | Synthesis method of tert-butyl 3-oxo-5-hydroxy-6-cyanohexanoate | |
| CN111138350A (en) | Asymmetric synthesis method of dexchlorpheniramine and dexbrompheniramine | |
| CN111777561A (en) | Preparation method and application of 4,6 dichloropyrimidine | |
| CN110698358A (en) | Synthesis of continuous oseltamivir phosphate | |
| CN104151232A (en) | Method for preparing etocoxib | |
| CN108084217A (en) | A kind of preparation method of 2,6- dichloros phenyl boric acid | |
| US20100160677A1 (en) | Process for preparation of 6-[3-(1-admantyl)-4-methoxyphenyl]-2-naphtoic acid. |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |