CN110156631A - A kind of continuous flow preparation method of 2,6- diethyl -4- methylaniline diazonium salt - Google Patents
A kind of continuous flow preparation method of 2,6- diethyl -4- methylaniline diazonium salt Download PDFInfo
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- CN110156631A CN110156631A CN201910530241.XA CN201910530241A CN110156631A CN 110156631 A CN110156631 A CN 110156631A CN 201910530241 A CN201910530241 A CN 201910530241A CN 110156631 A CN110156631 A CN 110156631A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C245/00—Compounds containing chains of at least two nitrogen atoms with at least one nitrogen-to-nitrogen multiple bond
- C07C245/20—Diazonium compounds
Abstract
The invention discloses one kind 2, the continuous flow preparation method of 6- diethyl -4- methylaniline diazonium salt, it is included in integrated reactor feed inlet and is continuously added to diazo reagent, acid and 2,6- diethyl -4- methylaniline, carry out diazo-reaction, 2,6- diethyl -4- methylaniline diazonium salt, which is continuously available, in integrated reactor discharge port carries out subsequent reactions.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 2,6- diethyl -4- methylaniline diazonium salt
Continuous flow preparation method.
Background technique
2,6- diethyl -4- methylaniline diazonium salt is the key intermediate of herbicide pinoxaden.
CN109134187A, CN106928253A, CN102395546A, CN108864144A are reported 2,6- bis- first
Ethyl -4- methylaniline first passes through still reaction preparation 2,6- diethyl -4- methylaniline diazonium salt, then its bromination is prepared 2,
The method of 6- diethyl -4- methyl bromobenzene.
These methods have the shortcomings that following significant:
(1) the still reaction security risk for preparing diazonium salt is big, and limitation production capacity is promoted.After diazo-reaction, in reaction kettle
It has a large amount of diazonium salt to exist, causes to explode since diazonium salt easily decomposes, so that existing in commercial process great
Security risk, so that the production capacity of limitation 2,6- diethyl -4- methylaniline diazonium salt is promoted.
(2) in still reaction, diazonium salt gradually increases, and system viscosity is gradually increased, and increases energy consumption, also limits
The production capacity of 2,6- diethyl -4- methylaniline diazonium salt is promoted.
(3) 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.
(4) due to preparing diazonium salt temperature is lower when, and it is anti-usually need to carry out as early as possible subsequent bromination after the completion of diazonium salt preparation
It answers, therefore the lower diazonium salt of temperature can make to need higher temperature when subsequent bromination, energy consumption is big.
It is, thus, sought for a kind of production safety 2,6- diethyl -4- that is efficient, easy to operate, being easy to large-scale production
Methylaniline diazonium salt production process.
Summary of the invention
To solve the above problems, the present invention provides the continuous flow systems of one kind 2,6- diethyl -4- methylaniline diazonium salt
Preparation Method, it is characterised in that: the method carries out in integrated reactor, continuous in the feed inlet of the integrated reactor
First material, second material and third material is added, is continuously available 2,6- diethyl-in the discharge port of the integrated reactor
4- methylaniline diazonium salt；
Contain diazo reagent in the first material, acid is contained in second material, contains 2,6- diethyl in third material
Base -4- methylaniline.
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 two 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 ° to 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 two to 15 sequentially connected independent fluid modules, and
The microreactor total volume of continuous current micro-reactor is 17mL~2250mL.
The reaction total time of the method is 0.05~60min.
In a specific embodiment of the invention, the total reaction volume of continuous current micro-reactor is that 17mL (is not counted in
2 module of warm area for temperature control), total time of the reaction is 4~300s, preferably 4~10s, more preferable 6~8s, most preferably
7.7s。
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, the diazo reagent and acid-mixed are closed, fully reacting or reaction not exclusively, resulting material again with
2,6- diethyl -4- methylaniline carries out diazo-reaction and generates corresponding diazonium salt.
Further, the diazo reagent is selected from nitrite or nitrosylsulfuric acid；The nitrite is selected from Asia
Lithium nitrate, sodium nitrite, potassium nitrite, ammonium nilrite, magnesium nitrite, barium nitrite or calcium nitrite, preferably sodium nitrite.
Further, the feed concentration of the diazo reagent is 10wt%~95wt%；Diazo reagent is nitrous acid
When sodium, feed concentration preferred 20wt%~35wt%, 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
Concentration preferred 30wt~48wt%, more preferable 48wt%.
Further, the molar ratio of 2, the 6- diethyl -4- methylaniline and diazo reagent is 1:1~10, preferably
1:1~2, more preferable 1:1.6~1.7.
The molar ratio of 2, the 6- diethyl -4- methylaniline and acid is 1:1~10, preferably 1:1~3, more preferable 1:2.
Further, the continuous flow synthesis technology carries out in the integrated reactor comprising 3 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 material through the pre- controlling temperature of warm area 2 are mixed in warm area 3, flows through warm area 3,
Diazo-reaction is wherein completed, diazonium salt is generated.
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 residence time of the warm area 1 is 2~23s, excellent 2.5~5.5s, more preferable 4.3s.
Further, the residence time of the warm area 3 is 2~18s, preferably 2~4s, more preferable 3.4s.
Wherein, in the calculating of previous reaction total time, the total time of reaction is the total of 3 residence time of warm area 1 and warm area
With, 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, the work of control temperature of charge is only played
With.In a particular embodiment, in order to simplify temperature control operation, the module of microreactor, but those skilled in the art are also used
All know, 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 2,6- diethyl -4- methylaniline, again is uninterruptedly added in the feed inlet of aforementioned integrated reactor
Diazotizing reagent, acid and bromide reagent.
When carrying out diazo-reaction by continuous stream mode, the prior art such as Org.Process Res.Dev., 2018,
22 (12), pp 1828-1834 usually first mixes arylamine with acid, then reacts with diazo reagent.But by reacting continuous flow
The screening test of hybrid mode finds, for the aniline 2 of specific structure of the present invention, for 6- diethyl -4- methylaniline, with
When acid first mixes, the salt of generation solubility in water phase is lower, causes entire continuous flow reaction efficiency relatively low.
If 6- diethyl -4- methylaniline is first mixed with diazo reagent using 2, easily it is divided into two-phase and is not easy to feed.
Accordingly, it is preferred that mode is first to close diazo reagent and acid-mixed, then carry out with 2,6- diethyl -4- methylaniline
Diazo-reaction generates corresponding diazonium salt.When diazo reagent and acid-mixed are closed, according to the difference of diazo reagent used and acid,
It can react and generate corresponding nitrous acid or nitrosyl.This kind of reaction is usually exothermic, passes through the thermal control stream of reaction unit
Body heat absorption pre-cooling, is conducive to the progress of lower step diazo-reaction.In entire continuous flow reaction process of the invention, relative to rear
Continuous diazo-reaction and bromination reaction, the control to the step hybrid reaction retention time is relatively unessential, and simultaneously should not
Ask certain reaction completely.
The diazo reagent is selected from nitrite or nitrosyl sulfate.The nitrite be selected from lithium nitrite,
Sodium nitrite, potassium nitrite, ammonium nilrite, magnesium nitrite, barium nitrite or calcium nitrite, preferably lower-cost nitrous acid
Sodium.
The feed concentration of the diazo reagent is 10wt%~95wt%,
When diazo reagent is sodium nitrite, feed concentration preferred 20wt%~30wt%, more preferable 25wt%.Work as concentration
When lower, phenol by-product content increases；When concentration is higher, has part diazonium and salt out, it is anti-to be unfavorable for entire continuous flow
Should carry out.
It is outstanding that the feed liquid of the diazo reagent is selected from diazo liquid reagent, diazo reagent slurry liquid, diazo reagent
Turbid, emulsion and solution, preferred aqueous solutions, conducive to the dissolution of subsequent diazonium salt, thus be conducive to entire continuous flow react into
Row.
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.
Preferred embodiment is first to mix hydrobromic acid with sodium nitrite, and nitrous acid is prepared in situ.It is anti-to prepare nitrous acid
The temperature answered is -15~25 DEG C.Step reaction is usually exothermic, passes through the thermal control fluid heat absorption control reaction temperature of reaction unit
Degree.Energy consumption is high if temperature is too low；If temperature is excessively high, nitrous acid is easily decomposed, to reduce the yield of entire continuous flow reaction.
Test discovery, at 0~15 DEG C, effect gap is little, therefore it is preferred that 0~15 DEG C.
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 and be unfavorable for reacting, especially when the reaction unit used is microreactor, it but will cause
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 hair
Existing, at 0~15 DEG C, effect gap is little, therefore it is preferred that 0~15 DEG C.Multiple batches of authentication is found, subsequent to carry out weight when at 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.
Preferred embodiment is that the temperature and next step of diazo reagent and acid-mixed conjunction carry out the temperature of diazo-reaction
It is identical, so that the temperature control effect of diazo-reaction is more preferably.
The temperature of the bromination reaction is 0~90 DEG C, and preferably 45~80 DEG C, in the temperature range, temperature is to reaction effect
It influences little.Due to brominated reaction process be it is exothermic, need higher temperature to cause, actual inside reaction temperature is higher.Temperature
The higher raising for being conducive to reaction selectivity is spent, but reacts excessively high, there is tar generation；The too low then phenol by-product content of temperature
Increase.
The molar ratio of 2, the 6- diethyl -4- methylaniline and diazo reagent is 1:1~10, preferred 1:1~2, more
It is preferred that 1:1.6~1.7.When using sodium nitrite as diazo reagent, sodium nitrite dosage is anti-between 1.6~1.7eq
Answer effect preferable, if dosage is lower than 1.6eq, raw material conversion is incomplete；If dosage is higher than 1.7eq, impurity and tar can contain
Amount increases, and makes the reduction of final product purity.
The molar ratio of 2, the 6- diethyl -4- methylaniline and acid is 1:1~10, preferably 1:1~3, more preferable 1:2.
When sour dosage is lower than 2eq, raw material conversion is incomplete；When sour dosage is higher than 2eq, by-products content increases, and tar content increases.
In conjunction with integrated reacting above-mentioned as preferred embodiment, the continuous flow synthesis technology is including 3
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 material through the pre- controlling temperature of warm area 2 are mixed in warm area 3, flows through warm area 3,
Diazo-reaction is wherein completed, diazonium salt is generated.
Meanwhile the present invention also provides the preparation methods of one kind 2,6- diethyl -4- methyl bromobenzene, by continuous flow above-mentioned
Preparation method prepares 2,6- diethyl -4- methyl bromide phenyl diazonium salt, and the discharge port of middle reactor is anti-as bromination in this way
2, the 6- diethyl -4- methyl bromide phenyl diazonium salt feed inlet answered, by 2,6- diethyl -4- methyl bromide phenyl diazonium salt and bromide reagent
Reaction, is prepared 2,6- diethyl -4- methyl bromobenzene.
The bromide reagent is selected from hydrobromic acid and/or metal bromide, and preferred metal bromide is sodium bromide or bromination
Potassium；It is preferred that also containing cuprous salt, molysite or ferrous salt, preferably sulfuric acid is ferrous.
2, the 6- diethyl -4- methyl bromobenzene that the present invention obtains is crude product, and post-processing can be isolated and purified further.Bromo is anti-
After answering, hexahydrotoluene is added and extracts split-phase, upper organic phase is respectively after washing, saturated sodium carbonate are washed, depressurize precipitation
Crude product is obtained, crude product is evaporated under reduced pressure (10mmHg) through oil pump, collects 80-90 DEG C of fraction and obtains 2, the 6- diethyl -4- of high-purity
Methyl bromobenzene.
The beneficial effects of the present invention are:
(1) production safety is efficient, does not have diazonium salt accumulation.
(2) easy to operate, production is efficient.
(3) system large viscosity in still reaction is solved the problems, such as.
(4) diazonium salt that continuous flow obtains directly discharges reacted with bromide reagent after, gained 2,6- diethyl -4- methyl bromide
Benzaldehyde 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.
Embodiment
As shown in Figure 1, by the HBr aqueous solution and concentration 25wt%NaNO of concentration 48wt%2Aqueous solution is passed through pre-cooling module
(warm area 1) hybrid reaction separately takes 2,6- diethyl -4- methylaniline to be passed through the pre-cooling of warm area 2.The material and warp of warm area 1 will be flowed through
The material of the pre- controlling temperature of warm area 2 mixes in warm area 3, flows through warm area 3, completes diazo-reaction wherein, generates in diazonium salt
Mesosome.
Intermediate diazonium salt goes out after reactor to be directly accessed bromo-reaction kettle carries out bromo-reaction at 80 DEG C.According to continuous
0.5eq FeSO is added in the dosage for 2, the 6- diethyl -4- methylaniline being passed through in bromo-reaction kettle in advance4.7H2O、
1.18eq 48%HBr, 3eq NaBr.After bromo-reaction, hexahydrotoluene is added and extracts split-phase, upper organic phase difference
Crude product is obtained after washing, saturated sodium carbonate are washed, depressurize precipitation, crude product is evaporated under reduced pressure (10mmHg) through oil pump, collects 80-90 DEG C
Fraction obtains 2,6- diethyl -4- methyl bromobenzene.
Response parameter and result are as shown in table 1 below.
Wherein, T1~T3 respectively indicates the temperature of warm area 1, warm area 2 and warm area 3；The residence time of t1 expression warm area 1；t3
Indicate the residence time of warm area 3；Material ratio is DEMA, HBr, NaNO2Molar ratio；DEMA indicates 2,6- diethyl -4-
Methylaniline；Product yield and purity are the yield and HPLC purity of 2,6- diethyl -4- methyl bromobenzene.
Residence time is calculated by throughput and corresponding module volume.
Table 1
The results show that product yield and purity are preferable when the temperature of warm area 3 is 5 DEG C.
According to the method for previous embodiment, throughput (residence time) is screened, response parameter and result are such as
Shown in the following table 2.
Table 2
The results show that product can obtain preferable yield and purity in the range of the above-mentioned residence time.
According to the method for previous embodiment, material ratio is screened, response parameter and result are as shown in table 3 below.
Table 3
The results show that effect is preferable when the molar ratio of 2,6- diethyl -4- methylanilines and HBr are 1:2；2,6- diethyl
Base -4- methylaniline and NaNO2Molar ratio be 1:1.7 when, effect is preferable.Preferred molar ratio of material example is 2,6- diethyl
Base -4- methylaniline: HBr:NaNO2=1:2:1.7.
According to the method for previous embodiment, fixed material molar ratio is 2,6- diethyl -4- methylaniline: HBr:
NaNO2=1:2:1.7.To HBr and NaNO2Concentration is screened, and response parameter and result are as shown in table 4 below.
Table 4
The results show that as hydrobromic acid concentration 48wt% and when sodium nitrite concentration is 25wt%, product yield and purity compared with
It is good.
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 being reduced to -10~-15 DEG C by 80 DEG C or so, a large amount of aniline salt out in system at this time, and viscosity is 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. one kind 2, the continuous flow preparation method of 6- diethyl -4- methylaniline diazonium salt, it is characterised in that: the method is one
It is carried out in body reactor, is continuously added to first material, second material and third object in the feed inlet of the integrated reactor
Material, is continuously available 2,6- diethyl -4- methylaniline diazonium salt in the discharge port of the integrated reactor；
Contain diazo reagent in the first material, acid is contained in second material, contains 2,6- diethyl -4- in third material
Methylaniline.
2. continuous flow preparation method according to claim 1, it is characterised in that: the integrated reactor uses module
Change structure, include multiple warm areas, each warm area independently includes more than one reactor module or reactor module group, described
Reactor module group be connected in series or in parallel by multiple reactor modules, be connected with each other between each warm area；Preferred integration
Reactor is continuous current micro-reactor.
3. continuous flow preparation method according to claim 2, it is characterised in that: the continuous current micro-reactor includes at least
Three sequentially connected independent fluid modules；Preferably, 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 25mL to 2250mL.
4. continuous flow preparation method according to claim 3, it is characterised in that: the total time of the reaction is, 0.05~
4~10 seconds, most preferably 6~8 seconds are more selected in 60 minutes, preferably 4~300 seconds.
5. continuous flow preparation method according to claim 3, it is characterised in that: the song in each individually fluid modules
Deflector body runner includes the bending of multiple bending angle with 90 ° to 180 °.
6. continuous flow preparation method according to claim 3, it is characterised in that: the company in each individually fluid modules
The continuous passage depth that continuous channel has from 0.8 millimeter to 3 millimeter；Continuous passage in each solely fluid modules have from
0.7 millimeter to 1.1 millimeters of continuous passage width.
7. continuous flow preparation method according to claim 3, it is characterised in that: continuous logical in each individually fluid modules
Road includes multiple continuous mixing chambers, and each continuous mixing chamber includes at least one flow shunt structure, each continuous mixing chamber tool
There is the chamber width greater than continuous passage width；Preferably, the chamber width of each continuous mixing chamber is 1 millimeter to 20 millimeters,
More preferable 3 to 15 millimeters.
8. continuous flow preparation method according to claim 1-7, it is characterised in that: first make the diazo reagent
It is closed with acid-mixed, not exclusively, resulting material carries out diazo-reaction with 2,6- diethyl -4- methylaniline again for fully reacting or reaction
Generate corresponding diazonium salt.
9. continuous flow preparation method according to claim 1-8, it is characterised in that: the diazo reagent is selected from
Nitrite or nitrosylsulfuric acid；The nitrite is selected from lithium nitrite, sodium nitrite, potassium nitrite, ammonium nilrite, Asia
Magnesium nitrate, 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 diazo reagent
Feed concentration is 10wt%~95wt%；When diazo reagent is sodium nitrite, the preferred 20wt%~35wt% 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 30wt~48wt% of the concentration of hydrobromic acid, more preferably
48wt%.
12. -11 described in any item continuous flow preparation methods according to claim 1, it is characterised in that: 2, the 6- diethyl -
The molar ratio of 4- methylaniline and diazo reagent is 1:1~10, preferably 1:1~2, more preferable 1:1.6~1.7；
The molar ratio of 2, the 6- diethyl -4- methylaniline and acid is 1:1~10, preferably 1:1~3, more preferable 1:2.
13. according to the described in any item continuous flow preparation methods of claim 1-12, it is characterised in that: the continuous flow synthesizes work
Skill carries out in the integrated reactor comprising 3 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 material through the pre- controlling temperature of warm area 2 are mixed in warm area 3, flows through warm area 3, wherein
Diazo-reaction is completed, diazonium salt is generated.
14. continuous flow preparation method according to claim 13, 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.
15. continuous flow preparation method according to claim 14, it is characterised in that: the residence time of the warm area 1 be 2~
23 seconds, preferably 2.5~5.5 seconds, more preferable 4.3 seconds；
The residence time of the warm area 3 is 2~18 seconds, preferably 2~4 seconds, more preferable 3.4 seconds.
16. one kind 2, the preparation method of 6- diethyl -4- methyl bromobenzene, it is characterised in that: according to any one of claim 1-15
The continuous flow preparation method prepares 2,6- diethyl -4- methyl bromide phenyl diazonium salt, in this way the discharging of middle reactor
2,6- diethyl -4- methyl bromide phenyl diazonium salt feed inlet of the mouth as bromination reaction, by 2,6- diethyl -4- methyl bromobenzene diazonium
Salt is reacted with bromide reagent, and 2,6- diethyl -4- methyl bromobenzene is prepared.
17. preparation method according to claim 16, it is characterised in that: the bromide reagent is selected from hydrobromic acid and/or gold
Belong to bromide, preferred metal bromide is sodium bromide or potassium bromide；It is preferred that also containing cuprous salt, molysite or ferrous salt, preferably
Ferrous sulfate.
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