CN110156560A - A method of preparing 2,6- diethyl -4- methyl bromobenzene - Google Patents
A method of preparing 2,6- diethyl -4- methyl bromobenzene Download PDFInfo
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- C07—ORGANIC CHEMISTRY
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- C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
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Abstract
The invention discloses one kind 2, the continuous flow preparation method of 6- diethyl -4- methyl bromobenzene, whole preparation process carries out in integrated reactor, integrated reactor feed inlet is continuously added to nitrite reagent, pure and mild acid prepares nitrous acid ester, again with 2,6- diethyl -4- methylaniline carries out diazo-reaction, and gained diazonium salt occurs bromo-reaction with bromide reagent again and is continuously available 2,6- diethyl -4- methyl bromobenzene in integrated reactor discharge port.Production process of the present invention is safe and efficient, does not cause high-risk diazonium salt accumulation, solves the problems, such as that still reaction system viscosity is big, and product yield and purity are higher, and technological operation is simple and efficient.
Description
Technical field
The present invention relates to the preparation methods of pesticide intermediate, are more particularly to the continuous of 2,6- diethyl -4- methyl bromobenzene
Flow preparation method.
Background technique
2,6- diethyl -4- methyl bromobenzene is the key intermediate of herbicide pinoxaden.
CN109134187A, CN106928253A, CN102395546A, CN108864144A knock off between reporting use
2,6- diethyl -4- methylaniline elder generation diazotising, then bromination are prepared 2,6- diethyl -4- methyl by skill (batch process)
The method of bromobenzene.
These methods have the shortcomings that following significant:
(1) security risk is big, and limitation production capacity is promoted.A large amount of diazonium salt accumulation is had after diazo-reaction, in reaction kettle,
Cause to explode since diazonium salt easily decomposes, so that there are great security risks in commercial process, so that 2 are limited,
The production capacity of 6- diethyl -4- methyl bromobenzene is promoted.
(2) energy consumption is big, high production cost.To guarantee safety in production, need when preparing diazonium salt at low temperature (- 5 DEG C)
Lower progress, increases energy consumption；Repeatedly heating and cooling operation in production process simultaneously, not only makes cumbersome, but also drops
Low production efficiency.
(3) interval batch operation low efficiency, reaction time are long.The above method needs first to prepare 2,6- diethyl -4- methyl
It, is then carried out bromination reaction by the corresponding diazonium salt of aniline in being slowly dropped to bromide reagent, and technical process needs multiple
Reaction kettle, which cooperates, to be operated, and a batch production generally requires multiple hours, and technological operation is cumbersome, and time-consuming for production, production
Low efficiency.
(4) by-products content is difficult to control.After diazonium salt is prepared, since next step bromination reaction temperature is higher, lead to
It often needs to be slowly dropped to diazonium salt in bromide reagent and carries out bromination reaction, reaction time consumption is long, easily influences the selectivity of reaction
And increase by-products content.
It is, thus, sought for a kind of production safety is efficient, 2,6- diethyl easy to operate, being easy to be mass produced high-purity
Base -4- methyl bromobenzene preparation method.
Summary of the invention
To solve the above problems, the present invention provides a kind of method for preparing 2,6- diethyl -4- methyl bromobenzene, the side
Method carries out in integrated reactor, is continuously added to first material, second material, in the feed inlet of the integrated reactor
3 material and 4 materials, including nitrous acid ester preparation reaction, diazo-reaction and the bromination reaction successively carried out, described one
The discharge port of body reactor is continuously available 2,6- diethyl -4- methyl bromobenzene；Contain nitrite in the first material, the
Contain acid and alcohol in two materials, 2,6- diethyl -4- methylaniline is contained in third material, is tried in 4 materials containing bromination
Agent.
Test discovery, when nitrite and acid are blended in the same material, final products yield is reduced.Work as nitrous acid
When salt and alcohol are blended in the same material, ultimate yield yield can also be reduced.
The integrated reactor uses modular construction, includes multiple warm areas, each warm area independently includes one
Above reactor module or reactor module group, the reactor module group is by multiple reactor module serial or parallel connection groups
At being connected with each other between each warm area.
Wherein, the preferred continuous current micro-reactor of the integrated reactor.
The continuous current micro-reactor includes at least three sequentially connected independent fluid modules.Each independent fluid modules
Including module inlet and module outlet, the module inlet and module outlet are in fluid communication；Each individually fluid modules include limit
The continuous passage being scheduled in the reaction volume of independent fluid modules, the continuous passage define the reaction volume from reaction volume
The tortuous fluid flow channel that the reaction volume of entrance to reaction volume exports, the reaction volume entrance and module outlet fluid connect
Logical, the reaction volume outlet is in fluid communication with module outlet.
Tortuous fluid flow channel in each individually fluid modules includes multiple having 90~180 ° of bending angle
Bending.
In continuous current micro-reactor, each individually fluid modules include the reaction volume being limited in independent fluid modules
In continuous passage.The continuous passage is defined from the module inlet of an independent fluid modules to an independent fluid modules
Module outlet tortuous fluid flow channel.As used herein, term " tortuous fluid course " refers to the upper limit in the horizontal direction
It is scheduled between substantially parallel wall and is limited to the fluid channel between substantially parallel surface, the flowing in vertical direction
Channel include it is multiple have be at least 90 °, the bending of preferably about 180 ° of bending angle.In this respect, the multiple bending
Lead to the variation of fluid flow direction, in a preferred embodiment, side of the fluid flow direction relative to independent fluid modules
Edge reverses completely.
The independent fluid modules are made of glass, ceramics or glass-ceramic.
Continuous passage in each individually fluid modules has the continuous passage depth from 0.8~3mm.
Continuous passage in each individually fluid modules has the continuous passage width from 0.7~1.1mm.Each list
Continuous passage in only fluid modules includes multiple continuous mixing chambers, and each continuous mixing chamber includes at least one flow shunt knot
Structure, each continuous mixing chamber have the chamber width greater than continuous passage width.
The chamber width of each continuous mixing chamber is 1~20mm, preferably 3~15mm.
Further, the continuous current micro-reactor includes three to 15 sequentially connected independent fluid modules, and
The microreactor total volume of continuous current micro-reactor is 25~2250mL.
The reaction total time of the method is 0.1~60min.
In a specific embodiment of the invention, the total reaction volume of continuous current micro-reactor is that 25.5mL (disregards
Enter 2 module of warm area for temperature control), reaction total time is 3~50s, preferably 5~20s, more preferable 5~15s.
In continuous current micro-reactor, each individually fluid modules can equipped with the thermal control fluid of their own temperature from
Movement controller, it can be advantageous to control reaction temperature, constitute warm area above-mentioned, and independently protect in each independent fluid modules
Hold reaction temperature.Thermal control fluid can be the liquid being arbitrarily easy to get, and with suitable heat exchange functional characteristic, have simultaneously
There are good flow behavior, such as viscosity, to pass through the thermal control volume of independent fluid modules.In a specific implementation of the invention
In mode, thermal control fluid is silicone oil.
The multiple types microchannel continuous flow reactor for meeting above-mentioned condition in the prior art can be used in the method for the present invention
It realizes, such as microchannel continuous flow reactor disclosed in CN102202774A, CN103328440A.
Further, mix the first material with second material, fully reacting or reaction are incomplete, resulting material
Diazonium salt corresponding with the progress diazo-reaction generation of third material again carries out bromination reaction with 4 materials and obtains 2,6- diethyl
Base -4- methyl bromobenzene.
Further, the nitrite is selected from lithium nitrite, sodium nitrite, potassium nitrite, magnesium nitrite, nitrous acid
Barium or calcium nitrite, preferably sodium nitrite.
Further, the feed concentration of the nitrite is 10wt%~95wt%；The nitrite is nitrous acid
When sodium, feed concentration preferred 20wt%~30wt%, more preferable 25wt%.
Further, the acid is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid or oxalic acid, preferably hydrobromic acid, hydrobromic acid
The preferred 48wt% of concentration.
Further, the alcohol is selected from C1-C8Alcohol, preferably methanol, ethyl alcohol, 1- propyl alcohol, 2- propyl alcohol, n-butyl alcohol, 2- butanol,
The tert-butyl alcohol, amylalcohol or isoamyl alcohol.
Further, the bromide reagent is selected from hydrobromic acid and/or metal bromide.
Further, metal bromide is sodium bromide or potassium bromide.
Further, cuprous salt, molysite or ferrous salt are also contained in 4 materials, preferably sulfuric acid is ferrous.
Further, the molar ratio of 2, the 6- diethyl -4- methylaniline and alcohol is 1:1~10, preferred 1:1~3, more
It is preferred that 1:2.5.
The molar ratio of the alcohol and acid is 1:1~5, preferably 1:1~3, more preferable 1:1.5.
The molar ratio of 2, the 6- diethyl -4- methylaniline and nitrite is 1:1~10, and preferred 1:2~5 are more excellent
Select 1:3.75.
The molar ratio of bromo element is 1:1~10 in 2, the 6- diethyl -4- methylaniline and the total dosage of bromide reagent, excellent
Select 1:2~6, more preferable 1:4.Bromination actual amount
Further, the continuous flow synthesis technology carries out in the integrated reactor comprising 4 warm areas, including with
Lower step:
(a) first material and second material are flowed through into 1 hybrid reaction of warm area, third material is in warm area 2 or flows through warm area 2
Pre- controlling temperature；
(b) material for flowing through warm area 1 and the material for flowing through warm area 2 are mixed in warm area 3, flows through warm area 3, it is complete wherein
At diazo-reaction, diazonium salt is generated；
(c) diazonium salt of generation is mixed with 4 materials in warm area 4, flows through warm area 4, completes bromo-reaction wherein,
Obtain 2,6- diethyl -4- methyl bromobenzene.
Further, the temperature of the warm area 1 is -15~25 DEG C, preferably 0~15 DEG C, more preferable 5 DEG C.
Further, the temperature of the warm area 2 is -15~25 DEG C, preferably 0~15 DEG C, more preferable 5 DEG C.
Further, the temperature of the warm area 3 is -15~25 DEG C, preferably 0~15 DEG C, more preferable 5 DEG C.
Further, the temperature of the warm area 4 is 0~90 DEG C, preferably 35~85 DEG C, more preferable 45 DEG C.
Further, the residence time of the warm area 1 is 3~18s, preferably 3~8s, more preferable 3.2s.
Further, the residence time of the warm area 3 is 2~15s, preferably 2~6s, more preferable 2.3s.
Further, the residence time of the warm area 4 is 1~12s, preferably 1~4s, more preferable 1.2s.
Wherein, in the calculating of previous reaction total time, the total time of reaction is the summation of 1,3,4 residence time of warm area,
And it is not counted in the residence time of warm area 2.The reason is that material does not react in warm area 2, only play a part of to control temperature of charge.
In a particular embodiment, in order to simplify temperature control operation, the module of microreactor is also used, but those skilled in the art know
Dawn, a variety of alternatives can be taken to realize identical effect, such as can be with the container of temperature control.
The process of continuous flow preparation method of the present invention is as follows:
Reaction raw materials alcohol, acid, nitrite, 2,6- diethyl is uninterruptedly added in the feed inlet of aforementioned integrated reactor
Base -4- methylaniline and bromide reagent.
The nitrite is selected from lithium nitrite, sodium nitrite, potassium nitrite, magnesium nitrite, barium nitrite or nitrous
Sour calcium, the sodium nitrite that preferably cost is relatively low and stability is high.
The feed concentration of the nitrite is 10wt%~95wt%, when nitrite is sodium nitrite, feed concentration
It is preferred that 20wt%~30wt%, more preferable 25wt%.When concentration is lower, phenol by-product content increases；When concentration is higher,
It has part diazonium to salt out, is unfavorable for entire continuous flow reaction and carries out.
The feed liquid of the nitrite is selected from liquid nitrite reagent, nitrite reagent slurry liquid, nitrite examination
Agent suspension, emulsion and solution, preferred aqueous solutions, conducive to the dissolution of subsequent diazonium salt, so that it is anti-to be conducive to entire continuous flow
Should carry out.
Since diazotizing subsequent reactions are bromination reactions, preferred hydrobromic acid, to reduce the introducing of New raxa impurity.It is described
The preferred 48wt% of the concentration of hydrobromic acid.Test discovery, reduces the concentration of hydrobromic acid, and the content of phenol by-product increases.
The temperature of the diazo-reaction is -15~25 DEG C.Due to diazotizing reaction process be it is exothermic, make thermal control stream
The temperature of body slightly below reacts required temperature, to remove extra heat from reaction mixture.The energy consumption if temperature is too low
Height, and easily salt out the diazonium generated, it is unfavorable for reacting, especially when the reaction unit used is microreactor, Geng Huizao
At the blocking of reaction module；If temperature is excessively high, diazonium salt is easily decomposed, to reduce the yield of entire continuous flow reaction.Test
It was found that effect gap is little at 0~15 DEG C, therefore it is preferred that 0~15 DEG C.Multiple batches of verifying discovery, it is subsequent to carry out weight when being lower than 5 DEG C
The diazonium salt that nitridation reaction generates is stablized, and reaction stability is higher between batch, and more preferable 5 DEG C.
The temperature of the bromination reaction is 0~90 DEG C, preferably 35~85 DEG C, more preferable 45 DEG C.It was reacted due to brominated
Journey be it is exothermic, need higher temperature to cause, actual inside reaction temperature is higher.Temperature is higher to be conducive to mentioning for reaction selectivity
Height, but react excessively high, there is tar generation；The too low then phenol by-product content of temperature increases.
The molar ratio of 2, the 6- diethyl -4- methylaniline and alcohol is 1:1~10, preferred 1:1~3, more preferable 1:
2.5.The molar ratio of the alcohol and acid is 1:1~5, preferably 1:1~3, more preferable 1:1.5.When sour dosage is lower than 1eq, raw material turns
Change incomplete；When sour dosage is higher than 1.5eq, by-products content increases, and tar content increases.Alcohol converts not exclusively less, and alcohol is more then
Reaction system is set to increase pressure.
The molar ratio of 2, the 6- diethyl -4- methylaniline and nitrite is 1:1~10, and preferred 1:2~5 are more excellent
Select 1:3.75.Salt is more, and blocking is precipitated, and the few then conversion of salt is incomplete.When nitrite is sodium nitrite, sodium nitrite dosage exists
Reaction effect is preferable between 1.5~4eq, if dosage is lower than 1.5eq, raw material conversion is incomplete；It is miscellaneous if dosage is higher than 4eq
Matter and tar meeting content increase, and make the reduction of final product purity.
In conjunction with integrated reacting above-mentioned as preferred embodiment, the continuous flow synthesis technology is including 4
It is carried out in the integrated reactor of warm area, comprising the following steps:
(a) first material and second material are flowed through into 1 hybrid reaction of warm area, third material is in warm area 2 or flows through warm area 2
Pre- controlling temperature；
(b) material for flowing through warm area 1 and the material for flowing through the pre- controlling temperature of warm area 2 are mixed in warm area 3, flow through warm area 3,
Diazo-reaction is completed wherein, generates diazonium salt；
(c) diazonium salt of generation is mixed with 4 materials in warm area 4, flows through warm area 4, completes bromo-reaction wherein,
Obtain 2,6- diethyl -4- methyl bromobenzene.
2, the 6- diethyl -4- methyl bromobenzene that the present invention obtains is crude product, and post-processing can be isolated and purified further.Such as it will
The product of outflow is linked into the collecting tank with cooling water temperature device, and hexahydrotoluene extraction, split-phase, organic phase warp is added
It is saturated NaHCO3Aqueous solution is washed, is washed, and 2, the 6- diethyl -4- methyl bromobenzene of high-purity is evaporated under reduced pressure to.
The beneficial effects of the present invention are:
(1) production process essential safety, high-risk diazonium salt are consumed immediately once generation, do not cause the accumulation of diazonium salt.
(2) easy to operate, production is efficient.
(3) system large viscosity in still reaction is solved the problems, such as.
(4) product yield and purity is high.
Obviously, above content according to the present invention is not being departed from according to the ordinary technical knowledge and customary means of this field
Under the premise of the above-mentioned basic fundamental thought of the present invention, the modification, replacement or change of other diversified forms can also be made.
The specific embodiment of form by the following examples remakes further specifically above content of the invention
It is bright.But the range that this should not be interpreted as to the above-mentioned theme of the present invention is only limitted to example below.It is all to be based on above content of the present invention
The technology realized all belongs to the scope of the present invention.
Detailed description of the invention
Fig. 1 is the reaction process schematic diagram of the embodiment of the present invention.
Specific embodiment
In following specific embodiments, purity is HPLC purity, and the residence time is in terms of module.The reaction unit used for
Healthy and free from worry microchannel G1 glass reactor, the reaction volume of each module are 8.5mL.
As shown in Figure 1, the process flow diagram that the present invention uses is as it appears from the above, contain 4 concatenated microchannel plates
Device module and a collecting tank with cooling water temperature device are answered, wherein raw material isoamyl alcohol, hydrobromic acid aqueous solution and nitrous acid
Sodium water solution is pumped into from first module, isoamyl nitrite is prepared in situ through first and second pieces of module reactions, in third
Another entrance of serial module structure is then pumped into raw material 2, and 6- diethyl -4- methylaniline, the diazonium salt of generation is then in the 4th mould
Bromo-reaction occurs in block, finally outflow enters in collecting tank from outlet.First, second, third and fourth module
Outside is respectively arranged with convenient for the external heat exchanger of regulation and control reaction temperature, and the heat transferring medium of external heat exchanger is thermally conductive
Silicone oil.
Embodiment 1
Preparation: if Fig. 1 assembles microchannel continuous flow reactor, by ferrous sulfate heptahydrate, sodium bromide and hydrobromic acid
The ratio of 0.2:1.5:1.7 prepares in molar ratio, obtains uniformly mixed solution.
Microchannel continuous flow reactor runs work: setting the flow parameter of each pump and the temperature ginseng of each warm area
Number so that 2,6- diethyl -4- methylanilines, isoamyl alcohol, hydrobromic acid and 25wt% sodium nitrite molar ratio be 1:
1.5:1.65:1.8, the mass flow for controlling isoamyl alcohol is 20g/min, mass flow 42g/min, the 25wt% nitrous of hydrobromic acid
Acid sodium aqueous solution mass flow is 75g/min, and the reaction temperature of the first and second module is 0 DEG C, is pumped into 2,6- diethyl -4- methyl
Aniline, control mass flow are 24.7g/min, and the reaction temperature of third block module is 5 DEG C, are pumped into ferrous sulfate heptahydrate, bromination
The control of the mass flow of sodium and hydrobromic acid mixed solution is 75g/min, and the reaction temperature of the 4th piece of module is 85 DEG C, and pressure is
0.4MPa。
The residence time of first module is 6.2s.
The residence time of third module is 4.6s.
The residence time of 4th module is 3.1s.
2,6- diethyl -4- methylaniline in reaction, ferrous sulfate heptahydrate, sodium bromide and hydrobromic acid molar ratio be 1:
0.2:1.5:1.7。
The overall reaction residence time of entire continuous flow reaction is 13.9s.
Post-reaction treatment: the product of outflow is linked into the collecting tank with cooling water temperature device, and methyl ring is added
Hexane extraction, split-phase, organic phase is through being saturated NaHCO3Aqueous solution is washed, is washed, and vacuum distillation obtains 2,6- diethyl -4- methyl bromide
Benzene, purity 95%, yield 86%.
Embodiment 2
Preparation: if Fig. 1 assembles microchannel continuous flow reactor, by ferrous sulfate heptahydrate, sodium bromide and hydrobromic acid
It (is 1), to obtain uniformly mixed solution with 2,6- diethyl -4- methylaniline that the ratio of 0.2:2.0:2.0, which prepares, in molar ratio.
Microchannel continuous flow reactor runs work: setting the flow parameter of each pump and the temperature ginseng of each warm area
Number so that 2,6- diethyl -4- methylanilines, isoamyl alcohol, hydrobromic acid and 25wt% sodium nitrite molar ratio be 1:
1.5:1.8:1.8, the mass flow for controlling isoamyl alcohol is 30g/min, and the mass flow 68.8g/min, 25wt% of hydrobromic acid are sub-
Sodium nitrate aqueous solution mass flow is 112.7g/min, and the reaction temperature of the first and second module is 0 DEG C, is pumped into 2,6- diethyl -4-
Methylaniline, control mass flow are 37g/min, and the reaction temperature of third block module is 5 DEG C, are pumped into ferrous sulfate heptahydrate, bromine
The mass flow control for changing sodium and hydrobromic acid mixed solution is 136g/min, and the reaction temperature of the 4th piece of module is 85 DEG C, pressure
For 0.8MPa.
The residence time of first module is 3.4s.
The residence time of third module is 2.3s.
The residence time of 4th module is 1.7s.
2,6- diethyl -4- methylaniline in reaction, ferrous sulfate heptahydrate, sodium bromide and hydrobromic acid molar ratio be 1:
0.2:2.0:2.0。
The overall reaction residence time of entire continuous flow reaction is 7.4s.
Post-reaction treatment: the product of outflow is linked into the collecting tank with cooling water temperature device, and methyl ring is added
Hexane extraction, split-phase, organic phase is through being saturated NaHCO3Aqueous solution is washed, is washed, and vacuum distillation obtains 2,6- diethyl -4- methyl bromide
Benzene, purity 97%, yield 80%.
Embodiment 3
Preparation: if Fig. 1 assembles microchannel continuous flow reactor, by ferrous sulfate heptahydrate, sodium bromide and hydrobromic acid
The ratio of 0.2:2.0:2.0 prepares in molar ratio, obtains uniformly mixed solution.
Microchannel continuous flow reactor runs work: setting the flow parameter of each pump and the temperature ginseng of each warm area
Number so that 2,6- diethyl -4- methylanilines, isoamyl alcohol, hydrobromic acid and 25wt% sodium nitrite molar ratio be 1:
2.5:3.75:3.75, the mass flow for controlling isoamyl alcohol is 30g/min, and the mass flow 86g/min, 25wt% of hydrobromic acid are sub-
Sodium nitrate aqueous solution mass flow is 140.8g/min, and the reaction temperature of the first and second module is 5 DEG C, is pumped into 2,6- diethyl -4-
Methylaniline, control mass flow are 22.2g/min, and the reaction temperature of third block module is 5 DEG C, be pumped into ferrous sulfate heptahydrate,
The control of the mass flow of sodium bromide and hydrobromic acid mixed solution is 82g/min, and the reaction temperature of the 4th piece of module is 45 DEG C, pressure
For 0.6MPa.2,6- diethyl -4- methylaniline and the molar ratio of bromo element in the total dosage of bromide reagent are
The residence time of first module is 3.2s.
The residence time of third module is 2.3s.
The residence time of 4th module is 1.2s.
2,6- diethyl -4- methylaniline in reaction, ferrous sulfate heptahydrate, sodium bromide and hydrobromic acid molar ratio be 1:
0.2:2.0:2.0。
The overall reaction residence time of entire continuous flow reaction is 6.7s.
Post-reaction treatment: the product of outflow is linked into the collecting tank with cooling water temperature device, and methyl ring is added
Hexane extraction, split-phase, organic phase is through being saturated NaHCO3Aqueous solution is washed, is washed, and vacuum distillation obtains 2,6- diethyl -4- methyl bromide
Benzene, purity 98%, yield 93%.
Embodiment 4
Preparation: if Fig. 1 assembles microchannel continuous flow reactor, by ferrous sulfate heptahydrate, sodium bromide and hydrobromic acid
The ratio of 0.2:0:1.7 prepares in molar ratio, obtains uniformly mixed solution.
Microchannel continuous flow reactor runs work: setting the flow parameter of each pump and the temperature ginseng of each warm area
Number so that 2,6- diethyl -4- methylanilines, isoamyl alcohol, hydrobromic acid and 25wt% sodium nitrite molar ratio be 1:
1.5:1.65:1.8, the mass flow for controlling isoamyl alcohol is 20g/min, mass flow 42g/min, the 25wt% nitrous of hydrobromic acid
Acid sodium aqueous solution mass flow is 75g/min, and the reaction temperature of the first and second module is 0 DEG C, is pumped into 2,6- diethyl -4- methyl
Aniline, control mass flow are 24.7g/min, and the reaction temperature of third block module is 5 DEG C, are pumped into ferrous sulfate heptahydrate, bromination
The control of the mass flow of sodium and hydrobromic acid mixed solution is 52g/min, and the reaction temperature of the 4th piece of module is 85 DEG C, and pressure is
0.4MPa.2,6- diethyl -4- methylaniline and the molar ratio of bromo element in the total dosage of bromide reagent are
The residence time of first module is 6.2s.
The residence time of third module is 4.6s.
The residence time of 4th module is 3.1s.
2,6- diethyl -4- methylaniline in reaction, ferrous sulfate heptahydrate, sodium bromide and hydrobromic acid molar ratio be 1:
0.2:2.0:1.7。
The overall reaction residence time of entire continuous flow reaction is 13.9s.
Post-reaction treatment: the product of outflow is linked into the collecting tank with cooling water temperature device, and methyl ring is added
Hexane extraction, split-phase, organic phase is through being saturated NaHCO3Aqueous solution is washed, is washed, and vacuum distillation obtains 2,6- diethyl -4- methyl bromide
Benzene, purity 71%, yield 30%.
Embodiment 5
Preparation: if Fig. 1 assembles microchannel continuous flow reactor, by ferrous sulfate heptahydrate, sodium bromide and hydrobromic acid
The ratio of 0.2:2.0:2.0 prepares in molar ratio, obtains uniformly mixed solution.
Microchannel continuous flow reactor runs work: setting the flow parameter of each pump and the temperature ginseng of each warm area
Number so that 2,6- diethyl -4- methylanilines, isoamyl alcohol, hydrobromic acid and 25wt% sodium nitrite molar ratio be 1:
1.5:1.8:1.8, the mass flow for controlling isoamyl alcohol is 30g/min, and the mass flow 68.8g/min, 25wt% of hydrobromic acid are sub-
Sodium nitrate aqueous solution mass flow is 112.7g/min, and the reaction temperature of the first and second module is 0 DEG C, is pumped into 2,6- diethyl -4-
Methylaniline, control mass flow are 37g/min, and the reaction temperature of third block module is 5 DEG C, are pumped into ferrous sulfate heptahydrate, bromine
The mass flow control for changing sodium and hydrobromic acid mixed solution is 136g/min, and the reaction temperature of the 4th piece of module is 25 DEG C, pressure
For 0.8MPa.2,6- diethyl -4- methylaniline and the molar ratio of bromo element in the total dosage of bromide reagent are
The residence time of first module is 3.4s.
The residence time of third module is 2.3s.
The residence time of 4th module is 1.7s.
2,6- diethyl -4- methylaniline in reaction, ferrous sulfate heptahydrate, sodium bromide and hydrobromic acid molar ratio be 1:
0.2:2.0:2.0。
The overall reaction residence time of entire continuous flow reaction is 7.4s.
Post-reaction treatment: the product of outflow is linked into the collecting tank with cooling water temperature device, and methyl ring is added
Hexane extraction, split-phase, organic phase is through being saturated NaHCO3Aqueous solution is washed, is washed, and vacuum distillation obtains 2,6- diethyl -4- methyl bromide
Benzene, purity 81%, yield 62%.
Embodiment 6
Preparation: if Fig. 1 assembles microchannel continuous flow reactor, by ferrous sulfate heptahydrate, sodium bromide and hydrobromic acid
The ratio of 0.2:2.0:2.0 prepares in molar ratio, obtains uniformly mixed solution.
Microchannel continuous flow reactor runs work: setting the flow parameter of each pump and the temperature ginseng of each warm area
Number so that 2,6- diethyl -4- methylanilines, isoamyl alcohol, hydrobromic acid and 25wt% sodium nitrite molar ratio be 1:
2.5:3.75:3.75, the mass flow for controlling isoamyl alcohol is 30g/min, and the mass flow 86g/min, 25wt% of hydrobromic acid are sub-
Sodium nitrate aqueous solution mass flow is 140.8g/min, and the reaction temperature of the first and second module is 25 DEG C, is pumped into 2,6- diethyl-
4- methylaniline, control mass flow are 22.2g/min, and the reaction temperature of third block module is 25 DEG C, and it is sub- to be pumped into seven water sulfuric acid
The mass flow of iron, sodium bromide and hydrobromic acid mixed solution controls 82g/min, and the reaction temperature of the 4th piece of module is 45 DEG C, pressure
Power is 0.6MPa.2,6- diethyl -4- methylaniline and the molar ratio of bromo element in the total dosage of bromide reagent are
The residence time of first module is 3.2s.
The residence time of third module is 2.3s.
The residence time of 4th module is 1.2s.
2,6- diethyl -4- methylaniline in reaction, ferrous sulfate heptahydrate, sodium bromide and hydrobromic acid molar ratio be 1:
0.2:2.0:2.0。
The overall reaction residence time of entire continuous flow reaction is 6.7s.
Post-reaction treatment: the product of outflow is linked into the collecting tank with cooling water temperature device, and methyl ring is added
Hexane extraction, split-phase, organic phase is through being saturated NaHCO3Aqueous solution is washed, is washed, and vacuum distillation obtains 2,6- diethyl -4- methyl bromide
Benzene, purity 79%, yield 53%.
Comparative example still reaction
First 2,6- diethyl -4- methylaniline (1eq) is added dropwise in 48wt% hydrobromic acid (3eq) aqueous solution in 70-80
Sufficiently reaction is at salt at DEG C, and system viscosity is gradually increased in salification process, and rear system solid content is added dropwise and reaches 40%, flowing
Property is poor.Then, system is reduced to -10~-15 DEG C by 80 DEG C or so, a large amount of aniline salt out in system at this time, viscosity into
One step becomes larger in starchiness, then 25% sodium nitrite in aqueous solution (1.1eq) progress diazo-reaction is slowly added dropwise.Separately take 1eq
48% hydrobromic acid, 0.5eq ferrous sulfate heptahydrate, 3eq sodium bromide, mixing is heated to 80 DEG C and prepares brominated reagent, by upper one
Counter be added dropwise in brominated reagent of diazotising of step preparation completes bromo-reaction, and process is added dropwise and is kept for 70-80 DEG C of temperature, after dripping
It is stirred to react 30min.Later, hexahydrotoluene is added and extracts split-phase, upper organic phase vacuum distillation recovered solvent, product yield
85%, purity 92%.
Claims (17)
1. a kind of method for preparing 2,6- diethyl -4- methyl bromobenzene, it is characterised in that: the method is in integrated reactor
It carries out, is continuously added to first material, second material, third material and 4 materials in the feed inlet of the integrated reactor,
Including nitrous acid ester preparation reaction, diazo-reaction and the bromination reaction successively carried out, in the discharging of the integrated reactor
Mouth is continuously available 2,6- diethyl -4- methyl bromobenzene；
Contain nitrite in the first material, acid and alcohol are contained in second material, contains 2,6- diethyl-in third material
4- methylaniline contains bromide reagent in 4 materials.
2. first according to the method described in claim 1, it is characterized by: the integrated reactor uses modularization knot
Structure includes multiple warm areas, and each warm area independently includes more than one reactor module or reactor module group, and described is anti-
It answers device module group to be connected in series or in parallel by multiple reactor modules, is connected with each other between each warm area；Preferred integrated reacting
Device is continuous current micro-reactor.
3. according to the method described in claim 2, it is characterized by: the continuous current micro-reactor successively connects including at least three
The independent fluid modules connect；Preferably, the continuous current micro-reactor includes three to 15 sequentially connected independent fluid moulds
Block, and the microreactor total volume of continuous current micro-reactor is 25~2250mL.
4. continuous flow preparation method according to claim 3, it is characterised in that: the total time of the reaction be 0.1~
60min, preferably 3~50s, more preferable 5~40s, most preferably 5~15s.
5. according to the method described in claim 3, it is characterized by: tortuous fluid flow channel in each individually fluid modules
Including it is multiple have 90~180 ° bending angle bending.
6. according to the method described in claim 3, it is characterized by: the continuous passage in each individually fluid modules has
From the continuous passage depth of 0.8~3mm；Continuous passage in each solely fluid modules has from the continuous of 0.7~1.1mm
Channel width.
7. according to the method described in claim 3, it is characterized by: the continuous passage in each individually fluid modules includes multiple
Continuous mixing chamber, each continuous mixing chamber includes at least one flow shunt structure, and each continuous mixing chamber is continuous with being greater than
The chamber width of channel width；Preferably, the chamber width of each continuous mixing chamber is 1~20mm, more preferable 3~15mm.
8. continuous flow preparation method according to claim 1-7, it is characterised in that: first make the first material with
Not exclusively, resulting material carries out diazotising with 2,6- diethyl -4- methylaniline again for second material mixing, fully reacting or reaction
Reaction generates corresponding diazonium salt, and diazonium salt is reacted with bromide reagent again generates 2,6- diethyl -4- methyl bromobenzene.
9. continuous flow preparation method according to claim 1-8, it is characterised in that: the nitrite is selected from
Lithium nitrite, sodium nitrite, potassium nitrite, magnesium nitrite, barium nitrite or calcium nitrite, preferably sodium nitrite.
10. -9 described in any item continuous flow preparation methods according to claim 1, it is characterised in that: the material of the nitrite
Liquid concentration is 10wt%~95wt%；When the nitrite is sodium nitrite, the preferred 20wt%~30wt% of feed concentration, more
It is preferred that 25wt%.
11. -10 described in any item continuous flow preparation methods according to claim 1, it is characterised in that: it is described acid selected from hydrochloric acid,
Hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid or oxalic acid, preferably hydrobromic acid, the preferred 48wt% of the concentration of hydrobromic acid.
12. -11 described in any item continuous flow preparation methods according to claim 1, it is characterised in that: the alcohol is selected from C1-C8
Alcohol, preferably methanol, ethyl alcohol, 1- propyl alcohol, 2- propyl alcohol, n-butyl alcohol, 2- butanol, the tert-butyl alcohol, amylalcohol or isoamyl alcohol.
13. -12 described in any item continuous flow preparation methods according to claim 1, it is characterised in that: the bromide reagent is selected from
Hydrobromic acid and/or metal bromide, preferred metal bromide are sodium bromide or potassium bromide；
Also contain cuprous salt, molysite or ferrous salt in the 4 materials, preferably sulfuric acid is ferrous.
14. -13 described in any item continuous flow preparation methods according to claim 1, it is characterised in that: 2, the 6- diethyl -
4- methylaniline is 1:1~10, preferably 1:1~3, more preferable 1:2.5 with the molar ratio with alcohol；
The molar ratio of the alcohol and acid is 1:1~5, preferably 1:1~3, more preferable 1:1.5；
The molar ratio of 2, the 6- diethyl -4- methylaniline and nitrite is 1:1~10, preferred 1:2~5, more preferable 1:
3.75；
The molar ratio of bromo element is 1:1~10 in 2, the 6- diethyl -4- methylaniline and the total dosage of bromide reagent, preferably 1:
2~6, more preferable 1:4.
15. according to the described in any item continuous flow preparation methods of claim 1-14, it is characterised in that: the continuous flow synthesizes work
Skill carries out in the integrated reactor comprising 4 warm areas, comprising the following steps:
(a) first material and second material are flowed through into 1 hybrid reaction of warm area, third material is in warm area 2 or flows through 2 pre-control of warm area
Temperature；
(b) material for flowing through warm area 1 and the material for flowing through the pre- controlling temperature of warm area 2 are mixed in warm area 3, warm area 3 is flowed through, at it
Middle completion diazo-reaction generates diazonium salt；
(c) diazonium salt of generation is mixed with 4 materials in warm area 4, flows through warm area 4, complete bromo-reaction wherein, obtains
2,6- diethyl -4- methyl bromobenzene.
16. continuous flow preparation method according to claim 15, it is characterised in that: the temperature of the warm area 1 is -15~25
DEG C, preferably 0~15 DEG C, more preferable 5 DEG C；
The temperature of the warm area 2 is -15~25 DEG C, preferably 0~15 DEG C, more preferable 5 DEG C；
The temperature of the warm area 3 is -15~25 DEG C, preferably 0~15 DEG C, more preferable 5 DEG C；
The temperature of the warm area 4 is 0~90 DEG C, preferably 35~85 DEG C, more preferable 45 DEG C.
17. continuous flow preparation method according to claim 16, it is characterised in that: the residence time of the warm area 1 be 3~
18s, preferably 3~8s, more preferable 3.2s；
The residence time of the warm area 3 is 2~15s, preferably 2~6s, more preferable 2.3s；
The residence time of the warm area 4 is 1~12s, preferably 1~4s, more preferable 1.2s.
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| CN113754512A (en) * | 2021-08-31 | 2021-12-07 | 浙江巍华新材料股份有限公司 | Preparation method of o-bromobenzotrifluoride |
| CN114181112A (en) * | 2021-12-13 | 2022-03-15 | 浙江中山化工集团股份有限公司 | Preparation method of 2, 6-diethyl-4-methylphenyl malononitrile |
| CN114907181A (en) * | 2021-02-09 | 2022-08-16 | 北京颖泰嘉和生物科技股份有限公司 | Device for sandmeyer reaction and method for continuously preparing 2, 6-diethyl-4-methyl bromobenzene |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114907181A (en) * | 2021-02-09 | 2022-08-16 | 北京颖泰嘉和生物科技股份有限公司 | Device for sandmeyer reaction and method for continuously preparing 2, 6-diethyl-4-methyl bromobenzene |
| CN114907181B (en) * | 2021-02-09 | 2024-04-23 | 北京颖泰嘉和生物科技股份有限公司 | Device for sandmeyer reaction and method for continuously preparing 2, 6-diethyl-4-methyl bromobenzene |
| CN113754512A (en) * | 2021-08-31 | 2021-12-07 | 浙江巍华新材料股份有限公司 | Preparation method of o-bromobenzotrifluoride |
| CN113754512B (en) * | 2021-08-31 | 2024-05-17 | 浙江巍华新材料股份有限公司 | Preparation method of o-bromobenzotrifluoride |
| CN114181112A (en) * | 2021-12-13 | 2022-03-15 | 浙江中山化工集团股份有限公司 | Preparation method of 2, 6-diethyl-4-methylphenyl malononitrile |
| CN114181112B (en) * | 2021-12-13 | 2024-01-09 | 浙江中山化工集团股份有限公司 | Preparation method of 2, 6-diethyl-4-methylphenyl malononitrile |
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