CN110218139A - A method of biphenyl derivatives are prepared using microchannel continuous flow reactor - Google Patents
A method of biphenyl derivatives are prepared using microchannel continuous flow reactor Download PDFInfo
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- C07C1/32—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon starting from compounds containing hetero-atoms other than or in addition to oxygen or halogen
- C07C1/325—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon starting from compounds containing hetero-atoms other than or in addition to oxygen or halogen the hetero-atom being a metal atom
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Abstract
The invention belongs to organic fines to synthesize field, the method for being related to preparing biphenyl derivatives using microchannel continuous flow reactor.The method uses microchannel continuous flow reaction unit, and grignard reagent, halobenzene, solvent and catalyst slurry feed mode, reaction obtains the biphenyl derivatives under 50 ~ 200 DEG C and the pressure of 0.1 ~ 2.0MPa.Has continuous feed feature in the preparation process of biphenyl derivatives of the present invention, reaction compartment is the channel of 100 μm ~ 10mm of depth, reaction temperature and pressure can flexibly be set compared with traditional intermittent reaction, reaction time from a few hours foreshorten to tens seconds, reaction yield is high, reaction side reaction is few, and mass transfer effect is good, and solves the problems such as reaction very exothermic bring safety.Present invention can apply to the large-scale productions of biphenyl derivatives, provide the preparation of industrialization route of a green economy environmental protection for such compound.
Description
Technical field
The present invention relates to fine organic compounds to synthesize field, in particular to using microchannel continuous flow reactor
The method for preparing biphenyl derivatives.
Background technique
Biphenyl compound plays a significant role in modern material and chemical industry, such as can prepare high-performance as monomer
Polyimides, liquid crystal type high molecular material, can be used as important ligand for asymmetry catalysis, be used for drug as intermediate
Molecule.It is to prepare the most important approach of biphenyl compound by the coupling of metal catalytic carbon-carbon bond, has up to the present developed
Very more coupling methods is used for carbon-carbon bond framework: Suzuki coupling, Kumada coupling, Ullmann coupling, Nigishi are even
Connection, Stille coupling, Hiyama coupling etc..But this kind of reaction usually requires the expensive metallo-organic compound precursor of preparation and uses
In coupling, needs to face huge cost using noble metal catalyst, severe reaction conditions, therefore industrialized production in the process and ask
Topic.
By taking the core monomer biphenyl dianhydride of polyimide material concern as an example, most effective preparation path is to pass through tetramethyl
Base biphenyl oxidation prepares biphenyl dianhydride.It has issued for a plurality of route at present for tetramethyl biphenyl, but exists in the process anti-
Answer condition harshness, expensive catalyst, the problems such as Atom economy is poor, the three wastes are more, heavy industrialization has difficulties.
The patent development of CN88107107.2 xylene halide is reacted with excess zinc, then in the organic Raney nickel of metal
Catalysis under reaction prepare tetramethyl biphenyl.The method needs to have not seen industrialization using large excess of zinc powder.
The patent of CN101638354, which discloses palladium charcoal and is catalyzed halogenated ortho-xylene, to be coupled to obtain the method for tetramethyl biphenyl, but in the process
It needs to be catalyzed using precious metal palladium, and reaction is needed using excessive lye, post-processing is cumbersome, and yield is lower, and economy is poor.
The patent of CN 103319296 disclose it is a kind of using palladium chtalyst oxidation ortho-xylene be coupled to obtain the method for tetramethyl biphenyl.This
Kind of method raw material is easy to get and Atom economy highest, but since direct activation C-H bond is extremely difficult, needs to use palladium as urging
Agent, terphenyl and multi-joint benzene compound may be generated by extending the reaction time or reinforcing reaction condition, and selectivity is lower.Previous generation
This reaction is studied by discipline Japanese firm's eighties, is controlled reaction yield due to selective problems in course of industrialization
7% or so, and severe reaction conditions, it is not industrialized.
Compared to other methods, the method for preparing tetramethyl biphenyl by grignard reagent Kumada coupling is relatively mild, preparation
The nickel compound of relative moderate can be used in the magnesium metal relative low price of grignard reagent, catalyst, is to be most suitable for extensive work
The route of industry.Early in 2004, Shanghai Institute of Organic Chemistry application No. is the patent of CN200410089450 disclose it is a kind of using spiral shell
The method that the ring organic nickel catalysis halogenated grignard reagent of dimethylbenzene prepares tetramethyl biphenyl.2013, Changchun Institute of Applied Chemistry CN
The patent of 103086838A discloses a kind of method for preparing tetramethyl biphenyl by Kumada coupling using grignard reagent, passes through
It uses no or little solvent and simplifies technique, obtain the tetramethyl biphenyl of moderate yield.2013, Changchun Institute of Applied Chemistry CN 103319296
The patent of B, which is disclosed, is catalyzed the method that the coupling of grignard reagent autoxidation prepares tetramethyl biphenyl by manganese.2014, Harbin
The patent of 104211559 A of polytechnical university CN discloses the Kumada coupling preparation four by alkyl tetrahydro furans as solvent
The method of methyl biphenyl is prepared for the tetramethyl biphenyl preparation of hectogram rank in embodiment.
But the method that the related Kumada coupling reported at present prepares tetramethyl biphenyl is in laboratory level, product system
It is standby to concentrate on gram-grade to hectogram grade range.This reaction very exothermic needs to carry out reaction system in reactant hybrid reaction
Good temperature control is to guarantee safety；Mass transfer influences reaction yield huge simultaneously, and mass-transfer efficiency difference will lead to reaction and receive
Rate reduces.
Existing report is intermittent reaction, and technique is traditional caldron process.It is industrial when being carried out using batch tank technique
When changing amplification, compared with laboratory room small-sized equipment, the mass transfer of reaction kettle is industrialized, heat transfer efficiency substantially reduces.Heat transfer efficiency is low
It is excessively high to will lead to local temperature, it is excessively high that mass transfer unevenly will lead to material local concentration, is easy to cause and rapidly heats up and cause anti-
Answer out of control, the finally danger such as generation flash, explosion.And with the progress of reaction, the concentration of reaction substrate can gradually be lower, reaction
Meeting is gradually slack-off or even stops, even if increasing the reaction time is also difficult to ensure that reactant converts completely.On the one hand unreacted is caused
The waste of a large amount of grignard reagents, on the other hand the post-processings such as be quenched since the high activity of grignard reagent will lead to there is high risk.
Therefore the batch tank technique based on prior art development is difficult to meet the requirement of this reaction safety and stability and highly effective reaction simultaneously.
To solve the above problems, applicant proposes the side that continuous flow prepares tetramethyl biphenyl on the basis of a large amount of explore
The heat transfer of reactant efficient mass transfer can be achieved at the same time in method, and reaction time from a few hours foreshorten to tens seconds, and reaction yield is high, secondary anti-
It should lack, reaction efficiency is obviously improved, and the method is further extended in other derivatives industryizatioies preparation of biphenyl.
In view of this, the present invention is specifically proposed.
Summary of the invention
It is an object of the invention to develop the new industrial process for preparing biphenyl derivatives.Pass through lattice in continuous flow apparatus
The coupling of formula reagent obtains biphenyl derivatives with high yield, overcomes the security risk of traditional batch autoclave technology, and can be significantly
Shorten the reaction time, improve product yield, provides that one safely controllable, environmentally protective, high-intelligentization, surely for such compound
Fixed efficient preparation of industrialization route.
Above-mentioned purpose to realize the present invention, the following technical scheme is adopted:
The method that biphenyl derivatives are prepared using microchannel continuous flow reactor, using microchannel continuous flow reactor according to following
Step carries out:
Using aryl grignard reagent shown in formula (1) as raw material A, using halogeno-benzene shown in formula (2) and catalyst as raw material B, with ether
Class is uniformly mixed to be prepared into slurry and squeeze into microchannel continuous-flow system according to a certain percentage and be reacted as solvent；It is pressing
Power is 0.1 ~ 2.0MPa, temperature is to react 5 ~ 100s at 50 ~ 200 DEG C to obtain reaction solution, post-treated and be refining to obtain formula (3) institute
The biphenyl derivatives shown；The catalyst includes transition metal salt and ligand；
Formula (1)Formula (2)Formula (3)；
Wherein, X indicates the halogen of Cl, Br, I or at least one of trifluoromethanesulfonic acid ester group；R and R ' is selected from alkyl, ether, nitre
At least one of base, alkenyl, aryl, substituted aryl, heterocycle；N indicates 1 ~ 3 integer.
Optionally, the alkyl can be selected from C1~C10Linear or branched alkyl group.
Optionally, the ether can be selected from C1~C6At least one of linear chain or branched chain ether.
Optionally, the C1~C10Alkyl is selected from methyl, ethyl, isopropyl, butyl；The C1~C6Ether be selected from methoxyl group,
Ethyoxyl, isopropoxy.
Optionally, the alkenyl can be selected from C2~C10Alkenyl, e.g., vinyl, acrylic, allyl, 1- cyclobutenyl, 1,
3- butadienyl, isobutenyl, pentenyl, hexenyl, heptenyl, octenyl etc..
Optionally, the solvent of the aryl grignard reagent solution can be selected from ethers, it is therefore preferable to methyltetrahydrofuran or
Cyclopentyl methyl ether.
Optionally, in the catalyst transition metal of transition metal salt in Pd, Ni, Cu, Fe, Co, Mn at least
It is a kind of.
Preferably, catalyst metals Fe, Ni.
Optionally, ligand is selected from least one of monodentate, bidentate, multidentate ligand in the catalyst；The ligand
Coordination atom is selected from least one of O, N, P, S.
Preferably, the ligand is selected from PPh3, at least one of acetylacetone,2,4-pentanedione.
Optionally, the stoichiometric ratio of the transition metal salt and the ligand is 2:1 ~ 1:2.
Optionally, the molar ratio of the catalyst and the aryl grignard reagent is 1:10 ~ 1:10000.
Optionally, the molar ratio of the aryl grignard reagent and the halogeno-benzene is 1:1 ~ 1:2.
Optionally, the molar ratio of the transition metal salt in the catalyst and the halogeno-benzene is 1:10 ~ 1:10000.
Optionally, the raw material A and the raw material B are fed using slurry, and flow rate of slurry is reactor liquid holdup V and react
The ratio of residence time t；
Wherein, reaction time t is 5 ~ 100s, and the liquid holdup V of reactor is 5 ~ 2500mL.
As an implementation, the method realizes biphenyl analog derivative by grignard reagent coupling and continuous Flow Technique
Preparation of industrialization (synthetic route is as the formula (4)), comprising the following steps:
Step 1: preparing grignard reagent and demarcate, as material A；Grignard reagent is prepared according to general format reagent synthetic method,
Row format reagent concentration of going forward side by side calibration；
Step 2: halogeno-benzene and catalyst are mixed and stirred for uniformly, as material B；
Step 3: reaction solution A and B being passed through into metering pump are respectively passed through in the warm-up block of micro passage reaction and preheat, then
It is reacted into reaction module；The temperature and pressure of reaction module are completed by external setting-up, according to different reactant controls
Make different reaction conditions；
Step 4: reaction solution the last one module complete cool down, subsequently into continuously be quenched device carry out reaction be quenched；It is quenched
Reaction solution afterwards is separated by continuous extraction apparatus, isolates organic phase and water phase；Organic phase enters rewinding kettle, inorganic phase
Into waste water treatment system；
Step 5: organic phase obtains biphenol compound product by subsequent distillation, rectifying, recrystallization means；Formula (4).
As an implementation, the grignard reagent is synthesized according to generic way, and reaction substrate is halogeno-benzene；Wherein halogen
Element is selected from Cl, Br, I, preferably Br or Cl；Magnesium source is magnesium chips or magnesium powder；Reaction dissolvent is ethers, preferably methyltetrahydrofuran or ring
Amyl methyl ether.
As an implementation, present invention process is continuous flow process, steady and continuous can run always, be different from tradition
Intermittent/batch reaction process.
As an implementation, reaction betides in micron order/grade channel of micro passage reaction in the present invention,
It is different from the meter level still reaction space of traditional reaction kettle.The diminution of reaction compartment functional dimension increases the several of molecular collision
Rate enhances mass transfer effect, to considerably increase reaction efficiency.
Optionally, the micro passage reaction is continuous flow micro passage reaction；The continuous flow micro passage reaction is by 1
~ 20 micro passage reaction module connection compositions；The inner passage depth of the continuous flow micro passage reaction be 100 μm ~
10mm。
Optionally, the modular structure of the micro passage reaction is once-through type channel design or enhancing mixed type channel knot
Structure.
Optionally, the once-through type channel design is micro-pipe shape or trench structure.
Optionally, the enhancing mixed type channel design is selected from T-type structure, spherical structure, water-drop-shaped structure, beveled structure
Or at least one of heart-shaped structure.
Optionally, the material of the module is wear-resistant material, and the wear-resistant material is selected from special glass, silicon carbide, Lan Bao
At least one of stone, corrosion resisting alloy, fluoropolymer.
As an implementation, the micro passage reaction includes warm-up block and reaction module, the warm-up block
Positioned at the reaction module upstream, the parameter setting of the warm-up block and the reaction module is completed by external setting-up.Respectively
Warm area temperature can be controlled accurately, and temperature fluctuation accurately controls within ± 0.2 DEG C, and can pass through independent control temperature
And adjust reaction depth.
Optionally, the preheating temperature of the warm-up block is 50 DEG C ~ 200 DEG C, preferably 80 DEG C ~ 160 DEG C.
Optionally, the reaction temperature of the reaction is 50 DEG C ~ 200 DEG C, preferably 80 DEG C ~ 160 DEG C.
As an implementation, present invention reaction can carry out under stress, and pressure size is adjustable, and pressure oscillation can essence
Really control is within ± 0.1bar.It is different from traditional handicraft grignard reagent reaction temperature and is limited by solvent boiling point, the technology of the present invention
Scheme can promote reaction temperature by pressurization, to accelerate reaction speed.
Optionally, the reaction pressure of the reaction is set as 0.1 ~ 2.0MPa, preferably 0.5 ~ 1.2MPa.
As an implementation, the reaction time than traditional handicraft shortens the 1-2 order of magnitude in the present invention, and can be accurate
Control is within ± 1s.Being different from the traditional handicraft reaction time is a few hours to a couple of days, and the reaction time of this technique is second grade.
Optionally, the reaction time that the reactant of the reaction stops in the continuous flow apparatus is 5 ~ 100s, preferably
10~30s。
As an implementation, successively by being continuously quenched with continuous extraction apparatus to have separated after material reaction
Machine phase and inorganic phase, are then refined.Continous way equipment for after-treatment is small in size, automatization level is high, heat release in the unit time
Measure it is small it is easily controllable, extraction need solvent it is few, this considerably reduce materials to the exposure of environment and the pressure of three-protection design.
Optionally, the quencher being continuously quenched is selected from water or protonic acid aqueous solution；The protonic acid aqueous solution is selected from
At least one of hydrochloric acid solution, ammonium chloride solution, sulfuric acid, phosphoric acid, acetic acid.
Optionally, the temperature that is quenched being quenched is 0 ~ 80 DEG C.
Optionally, the purification step include atmospheric distillation, rectification under vacuum, recrystallization, distillation and column chromatography at least
It is a kind of.
Compared with prior art, the invention has the benefit that
(1) catalyst of the invention has the characteristics that green high-efficient low cost.The embodiment of grignard reagent coupling of the present invention
It is middle to use Ni, Fe catalyst system.Ni, Fe are cheap and environmentally friendly and are easily recycled, and are preparation of industrialization biphenyl chemical combination
Object provides the reaction route of a green high-efficient.
(2) the method for the invention can realize essential safety.Using continuous Flow Technique, holding in reactor under same production capacity
Liquid measure reduces 3 orders of magnitude, and the continuous flow reactor of liquid holdup 2.5L is the production capacity that can reach volume 3m3 reaction kettle, accordingly
The risk that very exothermic in reaction process causes is substantially reduced, realizes the essential safety of technique.
(3) the method for the invention reaction time is short.The traditional handicraft reaction time was a few houres to several days, and continuous flow is reacted
Reaction can be completed in 5 ~ 100 seconds, greatly improve reaction rate.Fick's law of diffusion points out, reaction time and speed limit away from
From it is square directly proportional.Reaction molecular diffusion length shortens in micro-pipe, so that the reaction time be made to significantly reduce.
(4) the method for the invention mass-transfer efficiency is high, it can be achieved that molecule rank mixes.Present invention process material is in diameter
It is rotated under the microchannel constraint guidance of 100um-10mm, generates chaotic advection, two kinds of materials realize the time being thoroughly mixed
It is final to realize the other uniform mixing of molecular level less than 1s.And the reaction kettle of traditional handicraft leans on mechanical force in diameter centimetre or meter level
Space in mix, be difficult to realize the other mixing of molecular level.For mass-transfer efficiency, continuous flow microchannel technique compares caldron process
Two orders of magnitude or more are higher by, to promote reaction efficiency.
(5) the method for the invention material is without back mixing.Reactant is continuously promoted via channel in present invention process, after reaction
Material be detached from reaction chamber immediately, will not back mixing continue to contact with raw material, so that reduce that the reaction was continued and generate by-product can
Energy property, ensure that the high yield of product.
(6) the method for the invention temperature control is accurate, and temperature fluctuation is can be controlled within ± 0.2 DEG C.According to calculating, micro- reaction
Device area of surface-heat transfer is 20000 ㎡/m3, and traditional reactor is 1000 ㎡/m3.It is rapid that the elevator belt of heat exchange area carrys out heat
Transmitting, to realize accurate temperature control, while preventing due to temperature runaway bring risk.And traditional reaction unit temperature fluctuation compared with
Greatly, it is difficult to realize accurate temperature control.
(7) the method for the invention can adjust the temperature in differential responses stage by warm area.Initial reaction stage reactant concentration
Higher, reaction relative speed is higher；But reacting late phase reaction object concentration reduces, and reaction rate then will be greatly reduced.Format is tried
For agent coupling reaction, grignard reagent can not convert completely in traditional handicraft, this is because reaction late phase reaction object concentration reduces
Cause.Traditional handicraft reaction temperature is limited to solvent boiling point, can only by extend the reaction time or allow a certain reactant significantly
Excess lift conversion ratio, it is serious to increase the energy and time loss.Technique of the present invention promotes temperature in rear warm area, accelerates reaction
The reaction rate in later period, to ensure that transformation in planta rate.
(8) the method for the invention can refine control reaction pressure.For grignard reagent coupling reaction, traditional handicraft
For synthesis under normal pressure.Technique of the present invention can be implemented under stress, and carry out control accurate to pressure, and pressure oscillation is can be controlled in
Within the scope of ± 0.1bar.Compressive reaction can break through temperature in synthesis under normal pressure and be limited by solvent boiling point, to realize temperature -20
DEG C ~ 200 DEG C of any adjustings, so that reaction characteristics are adapted to, quickening reaction rate.
(9) the method for the invention high degree of automation, can seamless scale-up to large-scale industrial production.Product yield
Height, byproduct of reaction is few, purity is high, and consistency is good.The technique meets the requirement of intelligence manufacture and made in China 2025.
Detailed description of the invention
It, below will be to specific in order to illustrate more clearly of the specific embodiment of the invention or technical solution in the prior art
Embodiment or attached drawing needed to be used in the description of the prior art be briefly described, it should be apparent that, it is described below
Attached drawing is some embodiments of the present invention, for those of ordinary skill in the art, before not making the creative labor
It puts, is also possible to obtain other drawings based on these drawings.
Fig. 1 is according to a kind of process flow diagram of embodiment of the application.
Specific embodiment
Embodiment of the present invention is described in detail below in conjunction with embodiment, but those skilled in the art will
Understand, the following example is merely to illustrate the present invention, and is not construed as limiting the scope of the invention.It is not specified in embodiment specific
Condition person carries out according to conventional conditions or manufacturer's recommended conditions.Reagents or instruments used without specified manufacturer is
It can be with conventional products that are commercially available.
The preparation of 1 grignard reagent of experimental example
The preparation of the grignard reagent of 4- chloro-o-xylene: the standard operation prepared according to grignard reagent, to work under condition of nitrogen gas
A small amount of 4- chloro-o-xylene and solvent are added dropwise in magnesium chips after change, a small amount of iodine is added as initiator and heats initiation.Cause
Residue 4- chloro-o-xylene and solvent are added dropwise afterwards and maintains the reflux for state, continues the 2h that flows back after being added dropwise.Demarcate format examination
Agent, adjusting concentration are 2.5mol/L.It is denoted as 1#Grignard reagent.
The preparation of the grignard reagent of p-chlorotoluene: the standard operation prepared according to grignard reagent, to activation under condition of nitrogen gas
A small amount of p-chlorotoluene and solvent are added dropwise in magnesium chips afterwards, a small amount of iodine is added as initiator and heats initiation.It is added dropwise after initiation surplus
Remaining p-chlorotoluene and solvent simultaneously maintain the reflux for state, continue the 2h that flows back after being added dropwise.Grignard reagent is demarcated, adjusting concentration is
1.0mol/L.It is denoted as 2#Grignard reagent.
The preparation of the grignard reagent of 3- bromo ortho-xylene: the standard operation prepared according to grignard reagent, under condition of nitrogen gas
A small amount of 3- bromo ortho-xylene and solvent are added dropwise into the magnesium chips after activation, a small amount of iodine is added as initiator and heats initiation.
Residue 3- bromo ortho-xylene and solvent are added dropwise after initiation and maintains the reflux for state, continues the 2h that flows back after being added dropwise.Demarcate lattice
Formula reagent, adjusting concentration are 2.5mol/L.It is denoted as 3#Grignard reagent.
Preparation to the grignard reagent of methoxyl group chlorobenzene: the standard operation prepared according to grignard reagent, under condition of nitrogen gas to
It is added dropwise in magnesium chips after activation on a small quantity to methoxyl group chlorobenzene and solvent, a small amount of iodine is added as initiator and heats initiation.Cause
Residue is added dropwise to methoxyl group chlorobenzene and solvent afterwards and maintains the reflux for state, continues the 2h that flows back after being added dropwise.Grignard reagent is demarcated,
Adjusting concentration is 2.0mol/L.It is denoted as 4#Grignard reagent.
The preparation of 1 3,3 ', 4,4 '-tetramethyl biphenyl of embodiment
Typically, using process flow diagram shown in Fig. 1 as path, biphenol compound is prepared.Wherein continuous flow reactor
For microchannel continuous flow reactor (healthy and free from worry SiC-G1), microchannel continuous flow reactor internal structure is heart-shaped channel.It is wherein micro-
Channel diameter is 100 μm.
Preparation method 1
Take 1 that 10mol has been demarcated#The THF solution of grignard reagent takes 4- chloro neighbour's diformazan of 10mol as material A solution
The NiCl of benzene, 30mmol2, 60mmol PPh380 DEG C are mixed and heated to, 30min is heated, as material B solution；
Then A and B is respectively enterd according to molar ratio 1:1 by continuous flow reactor warm-up block by metering pump, controls pre- hot-die
120 DEG C of deblocking temperature；
After warm-up block, A and B solution enter hybrid reaction module, reaction temperature be set as 120 DEG C (preceding 80% modules)+
160 DEG C (rear 20% module), system pressure controls 6bar, and the flowing time in the continuous flow reactor of microchannel controls 100s；
Reactant enters continuous quenching module after refrigerating module is cooling, continues to be added 3% according to 1:1 volume ratio into reaction solution
Aqueous hydrochloric acid solution be quenched, rear temperature is quenched and is kept for 60 DEG C, then mixed liquor enter continuous extraction apparatus separation water phase and
Organic phase, water phase are directly entered waste water treatment system, and oil mutually enters rewinding kettle；
It is distilled to recover tetrahydrofuran, remaining high boiler material collects 3,3 ', 4,4 '-tetramethyl biphenyl of product by vacuum distillation,
Yield 1970g, gross production rate 94%.Reaction equation is as the formula (5):
Formula (5).
The preparation of 2 4,4 '-dimethyl diphenyl of embodiment
The process that preparation flow illustrates as shown in figure 1.
Take 2 that 10mol has been demarcated#The THF solution of grignard reagent as material A solution, take 10mol p-chlorotoluene,
The NiCl of 20mmol2, 40mmol PPh380 DEG C are mixed and heated to, 30min is heated, as material B solution；
Then A and B is respectively enterd according to molar ratio 1:1 by continuous flow reactor warm-up block by metering pump, controls pre- hot-die
140 DEG C of deblocking temperature；Wherein continuous flow reactor is microchannel continuous flow reactor (healthy and free from worry SiC-G1), the reaction of microchannel continuous flow
Device internal structure is heart-shaped channel；
After warm-up block, A and B solution enter hybrid reaction module, reaction temperature be set as 140 DEG C (preceding 80% modules)+
175 DEG C (rear 20% module), system pressure controls 10bar, and the flowing time in the continuous flow reactor of microchannel controls 30s；
Reactant enters continuous quenching module after refrigerating module is cooling, continues to be added 3% according to 1:1 volume ratio into reaction solution
Aqueous hydrochloric acid solution is quenched, and rear temperature is quenched and is kept for 60 DEG C, and then mixed liquor enters continuous extraction apparatus separation water phase and has
Machine phase, water phase are directly entered waste water treatment system, and oil mutually enters rewinding kettle；
It is distilled to recover tetrahydrofuran, surplus material in tetrahydrofuran and ethyl alcohol by being recrystallized to give 4,4 '-dimethyl diphenyls
Crystal, yield 1750g, gross production rate 96%.Reaction equation is as the formula (6):
Formula (6).
The preparation of 3 2,3 ', 2,3 '-tetramethyl biphenyl of embodiment
The process that preparation flow illustrates as shown in figure 1.
Take 10L(25mol) demarcated 3#The THF solution of grignard reagent takes the 3- chlorine of 30mol as material A solution
For ortho-xylene, the FeCl of 30mmol3, 60mmol acetylacetone,2,4-pentanedione is mixed and heated to 80 DEG C, and heating half an hour simultaneously stirs evenly work
For B solution；
Then A and B is proportionally respectively enterd by continuous flow reactor warm-up block, control format reagent and 3- by metering pump
Chloro-o-xylene ratio is 1:1.2, controls 150 DEG C of warm-up block temperature；Wherein continuous flow reactor is microchannel continuous flow
Reactor (healthy and free from worry SiC-G1), microchannel continuous flow reactor internal structure are heart-shaped channel；
After warm-up block, A and B solution enter hybrid reaction module, reaction temperature be set as 150 DEG C (preceding 70% modules)+
170 DEG C (rear 30% module), system pressure controls 7bar, and the flowing time in the continuous flow reactor of microchannel controls 20s；
Reactant enters continuous quenching module after refrigerating module is cooling, continues to be added 3% according to 1:1 volume ratio into reaction solution
Aqueous hydrochloric acid solution is quenched, and rear temperature is quenched and is kept for 60 DEG C, and then mixed liquor enters continuous extraction apparatus separation water phase and has
Machine phase, water phase are directly entered waste water treatment system, and oil mutually enters rewinding kettle；
It is distilled to recover tetrahydrofuran, surplus material collects 2,3 ', 2,3 '-tetramethyl biphenyl of product, yield by vacuum distillation
4672g, gross production rate 90%.Reaction equation is as the formula (7):
Formula (7).
The preparation of 4 4,4 '-dimethoxy-biphenyl of embodiment
The process that preparation flow illustrates as shown in figure 1.
Take 5.0L(10mol) demarcated 4#The methylcyclopentyl ethereal solution of grignard reagent takes as material A solution
The NiCl to methoxyl group chlorobenzene, 50mmol 1426g(10mol)2, 100mmol PPh380 DEG C are mixed and heated to, heating
30min, as material B solution；
Then A and B is respectively enterd according to molar ratio 1:1 by continuous flow reactor warm-up block by metering pump, controls pre- hot-die
90 DEG C of deblocking temperature；Wherein continuous flow reactor is microchannel continuous flow reactor (healthy and free from worry SiC-G1), the reaction of microchannel continuous flow
Device internal structure is heart-shaped channel；
Enter hybrid reaction module by A after warm-up block and B solution, reaction temperature is set as 90 DEG C of (preceding 70% modules)+130
DEG C (rear 30% module), system pressure controls 4.5bar, and the flowing time in the continuous flow reactor of microchannel controls 300s；
Reactant enters continuous quenching module after refrigerating module is cooling, continues to be added 3% according to 1:1 volume ratio into reaction solution
Aqueous hydrochloric acid solution is quenched, and rear temperature is quenched and is kept for 60 DEG C, and then mixed liquor enters continuous extraction apparatus separation water phase and has
Machine phase, water phase are directly entered waste water treatment system, and oil mutually enters rewinding kettle；
It is distilled to recover tetrahydrofuran, remaining high boiler material collects 4,4 '-dimethoxy-biphenyl of product, yield by vacuum distillation
1970g, gross production rate 92%.Reaction equation is as the formula (8):
Formula (8).
Embodiment 5 ~ 8
Typically, it for the preparation of 4,4 '-dimethoxy-biphenyls, is prepared with step same as Example 4, it is different
Place is, has converted each reaction condition, and as shown in table 1, the reaction condition of transformation is respectively as follows:
On the basis of embodiment 4, the condition of embodiment 5 ~ 8 changes table 1
Finally, it should be noted that the above embodiments are only used to illustrate the technical solution of the present invention., rather than its limitations；Although ginseng
According to foregoing embodiments, invention is explained in detail, but those skilled in the art should understand that: it is still
It is possible to modify the technical solutions described in the foregoing embodiments, or some or all of the technical features is carried out
Equivalent replacement；And these are modified or replaceed, it does not separate the essence of the corresponding technical solution various embodiments of the present invention technical side
The range of case.
Claims (10)
1. a kind of method that microchannel continuous flow prepares biphenyl derivatives, which is characterized in that use microchannel continuous flow reactor
It carries out as steps described below:
Using aryl grignard reagent shown in formula (1) as raw material A, using halogeno-benzene shown in formula (2) and catalyst as raw material B, with ether
Class is uniformly mixed to be prepared into slurry and squeeze into microchannel continuous-flow system in proportion and be reacted as solvent；It is 0.1 in pressure
~ 2.0MPa, temperature are that 5 ~ 100s of reaction obtains reaction solution at 50 ~ 200 DEG C, post-treated and be refining to obtain shown in formula (3) and join
Benzene derivative；
The catalyst includes transition metal salt and ligand；
Formula (1)Formula (2)Formula (3)；
Wherein, X indicates at least one of halogen or trifluoromethanesulfonic acid ester group selected from Cl, Br, I；R and R ' be selected from alkyl, ether,
At least one of nitro, alkenyl, aryl, substituted aryl, heterocycle；N indicates 1 ~ 3 integer.
2. the method as described in claim 1, which is characterized in that transition metal in the transition metal salt be selected from Pd, Ni,
At least one of Cu, Fe, Co, Mn.
3. the method as described in claim 1, which is characterized in that the ligand in monodentate, bidentate, multidentate ligand at least
The coordination atom of one kind, the ligand is selected from least one of O, N, P, S.
4. the method as described in claim 1, which is characterized in that the molar ratio of the aryl grignard reagent and the halogeno-benzene is
1:1~1:2。
5. the method as described in claim 1, which is characterized in that transition metal salt and the halogeno-benzene in the catalyst
Molar ratio is 1:10 ~ 1:10000.
6. the method as described in claim 1, which is characterized in that the raw material A and the raw material B are fed using slurry, slurry
Flow velocity is the ratio of reactor liquid holdup V and reaction time t；
Wherein, reaction time t is 5 ~ 100s, and the liquid holdup V of reactor is 5 ~ 2500mL.
7. the method as described in claim 1, which is characterized in that the micro passage reaction is continuous flow micro passage reaction；
The continuous flow micro passage reaction is made of 1 ~ 20 micro passage reaction module connection；
The inner passage depth of the continuous flow micro passage reaction is 100 μm ~ 10mm.
8. the method for claim 7, which is characterized in that the modular structure of the micro passage reaction is micro-pipe shape knot
One of which in structure, trench structure, T-type structure, spherical structure, water-drop-shaped structure, beveled structure or heart-shaped structure；
The material of the micro passage reaction be special glass, silicon carbide, sapphire, corrosion resisting alloy, it is fluoropolymer-containing its
Middle one kind.
9. the method as described in claim 1, which is characterized in that the post-processing is organic to separate including being continuously quenched and extracting
Phase and inorganic phase；
The quencher being continuously quenched is selected from water or protonic acid aqueous solution；The protonic acid aqueous solution is selected from hydrochloric acid solution, chlorine
Change at least one of ammonium salt solution, sulfuric acid, phosphoric acid, acetic acid；
The temperature that is quenched being quenched is 0 ~ 80 DEG C.
10. the method as described in claim 1, which is characterized in that it is described purification include atmospheric distillation, rectification under vacuum, recrystallization,
Distillation and column chromatography for separation purification means.
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| CN111285749A (en) * | 2020-03-26 | 2020-06-16 | 阮楚君 | Improved method for preparing biphenyl derivative by micro-channel continuous flow |
| CN113717019A (en) * | 2021-09-06 | 2021-11-30 | 哈尔滨工业大学（深圳） | Continuous flow reaction method for asymmetric allyl alkylation reaction |
| CN115025731A (en) * | 2022-07-12 | 2022-09-09 | 辽宁石化职业技术学院 | Continuous production device and process of o-phenylphenol |
| CN115611769A (en) * | 2021-07-16 | 2023-01-17 | 赛诺威(厦门)科技有限公司 | Method and device for synthesizing sartanbiphenyl by continuous flow |
| CN116102390A (en) * | 2023-02-14 | 2023-05-12 | 西安凯立新材料股份有限公司 | Method for synthesizing biphenyl compounds by adopting micro-channel continuous flow reactor |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111285749A (en) * | 2020-03-26 | 2020-06-16 | 阮楚君 | Improved method for preparing biphenyl derivative by micro-channel continuous flow |
| CN111285749B (en) * | 2020-03-26 | 2021-04-20 | 山东冠森高分子材料科技股份有限公司 | Improved method for preparing biphenyl derivative by micro-channel continuous flow |
| CN115611769A (en) * | 2021-07-16 | 2023-01-17 | 赛诺威(厦门)科技有限公司 | Method and device for synthesizing sartanbiphenyl by continuous flow |
| CN113717019A (en) * | 2021-09-06 | 2021-11-30 | 哈尔滨工业大学（深圳） | Continuous flow reaction method for asymmetric allyl alkylation reaction |
| CN115025731A (en) * | 2022-07-12 | 2022-09-09 | 辽宁石化职业技术学院 | Continuous production device and process of o-phenylphenol |
| CN116102390A (en) * | 2023-02-14 | 2023-05-12 | 西安凯立新材料股份有限公司 | Method for synthesizing biphenyl compounds by adopting micro-channel continuous flow reactor |
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Application publication date: 20190910 |