CN110117216B - Continuous flow preparation method of 2, 6-diethyl-4-methyl bromobenzene - Google Patents
Continuous flow preparation method of 2, 6-diethyl-4-methyl bromobenzene Download PDFInfo
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- CN110117216B CN110117216B CN201910530204.9A CN201910530204A CN110117216B CN 110117216 B CN110117216 B CN 110117216B CN 201910530204 A CN201910530204 A CN 201910530204A CN 110117216 B CN110117216 B CN 110117216B
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Abstract
The invention discloses a continuous flow preparation method of 2, 6-diethyl-4-methyl bromobenzene, which comprises the steps of continuously adding diazotization reagent, acid and 2, 6-diethyl-4-methyl aniline into a feed inlet of an integrated reactor for diazotization reaction, carrying out bromination reaction on the obtained diazonium salt and bromination reagent, continuously obtaining a crude product of 2, 6-diethyl-4-methyl bromobenzene at a discharge outlet of the integrated reactor, adding methylcyclohexane for extraction and phase separation, and carrying out water washing, saturated sodium carbonate washing and reduced pressure desolventization on an organic phase to obtain the 2, 6-diethyl-4-methyl bromobenzene. The production process is safe and efficient, does not cause high-risk heavy nitrogen salt accumulation, solves the problem of high viscosity of a kettle type reaction system, and has high product yield and purity, and simple and efficient process operation.
Description
Technical Field
The invention relates to a preparation method of a pesticide intermediate, in particular to a continuous flow preparation method of 2, 6-diethyl-4-methyl bromobenzene.
Background
2, 6-diethyl-4-methylbromobenzene is a key intermediate of the herbicide pinoxaden.
CN109134187A, CN106928253A, CN102395546A and CN108864144A all report a method for preparing 2, 6-diethyl-4-methyl bromobenzene by diazotizing 2, 6-diethyl-4-methyl aniline and brominating the diazotized 2, 6-diethyl-4-methyl bromobenzene by a batch process.
These methods suffer from the following significant disadvantages:
(1) the potential safety hazard is big, and the limited productivity promotes. After the diazotization reaction, a large amount of diazonium salt exists in the reaction kettle, and the diazonium salt is easy to decompose and causes explosion, so that great potential safety hazard exists in the industrial production process, and the improvement of the capacity of the 2, 6-diethyl-4-methyl bromobenzene is limited.
(2) High energy consumption and high production cost. In order to ensure safe production, the preparation of the diazonium salt needs to be carried out at low temperature (-5 ℃), thus increasing the energy consumption; meanwhile, the temperature is increased and decreased for many times in the production process, so that the operation is complicated, and the production efficiency is reduced.
(3) The batch operation efficiency is low, and the reaction time is long. The method needs to prepare the diazonium salt corresponding to the 2, 6-diethyl-4-methylaniline first and then slowly dropwise add the diazonium salt into a bromination reagent for bromination reaction, the technological process needs a plurality of reaction kettles to be matched with one another for operation, one batch of production often needs a plurality of hours, the technological operation is complicated, the production consumes a long time, and the production efficiency is low.
(4) The content of by-products is difficult to control. After the diazonium salt is prepared, because the temperature of the next bromination reaction is higher, the diazonium salt is usually required to be slowly added into a bromination reagent dropwise for bromination reaction, the reaction is long in time consumption, and the selectivity of the reaction is easily influenced, so that the content of byproducts is increased.
Therefore, a preparation method which is safe and efficient in production, simple in operation and easy for large-scale production of high-purity 2, 6-diethyl-4-methylbromobenzene needs to be found.
Disclosure of Invention
In order to solve the problems, the invention provides a continuous flow preparation method of 2, 6-diethyl-4-methyl bromobenzene, which is carried out in an integrated reactor, wherein a first material, a second material, a third material and a fourth material are continuously added into a feed inlet of the integrated reactor, diazotization and bromination reactions are sequentially carried out, and 2, 6-diethyl-4-methyl bromobenzene is continuously obtained at a discharge outlet of the integrated reactor;
the first material contains a diazotization reagent, the second material contains an acid, the third material contains 2, 6-diethyl-4-methylaniline, and the fourth material contains a bromination reagent.
The integrated reactor adopts a modular structure and comprises a plurality of temperature zones, each temperature zone independently comprises more than one reactor module or reactor module group, the reactor module group is formed by connecting a plurality of reactor modules in series or in parallel, and the temperature zones are mutually connected.
Wherein the integrated reactor is preferably a continuous flow microreactor.
The continuous-flow microreactor comprises at least three individual fluidic modules connected in series. Each individual fluidic module includes a module inlet and a module outlet, the module inlet in fluid communication with the module outlet; each individual fluidic module includes a continuous channel defined in the reaction volume of the individual fluidic module, the continuous channel defining a tortuous fluid flow path from a reaction volume inlet of the reaction volume in fluid communication with the module outlet to a reaction volume outlet of the reaction volume in fluid communication with the module outlet.
The tortuous fluid flow channels in each individual fluid module include a plurality of bends having bend angles of 90 ° to 180 °.
In a continuous-flow microreactor, each individual fluidic module comprises a continuous channel defined in a reaction volume in the individual fluidic module. The continuous channel defines a tortuous fluid flow path from a module inlet of an individual fluidic module to a module outlet of an individual fluidic module. As used herein, the term "tortuous fluid flow path" refers to a fluid passageway defined between substantially parallel walls in a horizontal direction and substantially parallel surfaces in a vertical direction, the fluid passageway including a plurality of bends having a bend angle of at least 90 °, and preferably about 180 °. In this regard, the plurality of bends result in a change in fluid flow direction, which in a preferred embodiment is completely reversed relative to the edges of the individual fluid modules.
The individual fluidic modules are made of glass, ceramic, or glass-ceramic.
The continuous channels in each individual fluidic module have a continuous channel depth of from 0.8-3 mm.
The continuous channel in each individual fluidic module has a continuous channel width of from 0.7 to 1.1 mm. The continuous channel in each individual fluidic module includes a plurality of continuous mixing chambers, each continuous mixing chamber including at least one flow splitting structure, each continuous mixing chamber having a chamber width greater than the continuous channel width.
The chamber width of each continuous mixing chamber is 1-20 mm, preferably 3-15 mm.
Further, the continuous-flow microreactor comprises three to fifteen individual fluidic modules connected in series, and the continuous-flow microreactor has a microreactor total volume of 25mL to 2250 mL.
The total reaction time of the method is 0.1-60 min.
In a specific embodiment of the invention, the total reaction volume of the continuous-flow microreactor is 25.5mL (excluding the temperature zone 2 module for temperature control), and the total reaction time is 7-54 s, preferably 7-17 s, and more preferably 14-15 s.
In a continuous-flow microreactor, each individual fluidic module can be equipped with its own automatic temperature control of the thermal control fluid, the reaction temperature can advantageously be controlled, the aforementioned temperature zones are formed, and the reaction temperature is maintained independently in the individual fluidic modules. The thermal control fluid may be any readily available liquid having suitable heat exchange functional characteristics while having good flow characteristics, such as viscosity, to pass through the thermal control volume of the individual fluid modules. In one embodiment of the present invention, the thermal control fluid is silicone oil.
The process of the present invention may be carried out using various types of microchannel continuous flow reactors known in the art which meet the above conditions, such as the microchannel continuous flow reactors disclosed in CN102202774A, CN 103328440A.
Further, the diazotization reagent is mixed with acid, the reaction is complete or incomplete, and the obtained material and 2, 6-diethyl-4-methylaniline are subjected to diazotization reaction to generate corresponding diazonium salt.
Further, the diazotizing agent is selected from nitrite or nitrosylsulfuric acid; the nitrite is selected from lithium nitrite, sodium nitrite, potassium nitrite, ammonium nitrite, magnesium nitrite, barium nitrite or calcium nitrite, preferably sodium nitrite.
Further, the concentration of the diazotization reagent feed liquid is 10-95 wt%; when the diazotizing agent is sodium nitrite, the concentration of the feed liquid is preferably 20 wt% to 30 wt%, more preferably 25 wt%.
Further, the acid is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid or oxalic acid, preferably hydrobromic acid, the concentration of hydrobromic acid is preferably 48 wt%.
Further, the brominating reagent is selected from hydrobromic acid and/or a metal bromide.
Further, the metal bromide is sodium bromide or potassium bromide.
Furthermore, the fourth material also contains cuprous salt, ferric salt or ferrous salt, preferably ferrous sulfate.
Further, the first material also contains metal bromide to increase the concentration of bromide ions in the subsequent bromination reaction.
Further, the molar ratio of the 2, 6-diethyl-4-methylaniline to the diazotizing agent is 1: 1-10, preferably 1: 1-2, and more preferably 1: 1.6-1.7.
The molar ratio of the 2, 6-diethyl-4-methylaniline to the acid is 1: 1-10, preferably 1: 1-3, and more preferably 1: 2.
The molar ratio of the 2, 6-diethyl-4-methylaniline to the bromine element in the total using amount of the brominating reagent is 1: 1-10, preferably 1: 2-6, and more preferably 1: 4.
Further, the continuous flow synthesis process is carried out in an integrated reactor comprising 4 temperature zones, and comprises the following steps:
(a) mixing and reacting the first material and the second material through a temperature zone 1, and pre-controlling the temperature of the third material in the temperature zone 2 or flowing through the temperature zone 2;
(b) mixing the material flowing through the temperature zone 1 and the material with the temperature pre-controlled by the temperature zone 2 in the temperature zone 3, flowing through the temperature zone 3, and completing diazotization reaction in the temperature zone to generate diazonium salt;
(c) and mixing the generated diazonium salt with a fourth material in a temperature zone 4, and allowing the mixture to flow through the temperature zone 4 to complete bromination reaction to obtain 2, 6-diethyl-4-methyl bromobenzene.
Further, the temperature of the temperature zone 1 is-15 to 25 ℃, preferably 0 to 15 ℃, and more preferably 5 ℃;
further, the temperature of the temperature zone 2 is-15 to 25 ℃, preferably 0 to 15 ℃, and more preferably 5 ℃;
further, the temperature of the temperature zone 3 is-15 to 25 ℃, preferably 0 to 15 ℃, and more preferably 5 ℃;
further, the temperature of the temperature zone 4 is 0-90 ℃, preferably 45-80 ℃, and more preferably 80 ℃.
Further, the residence time of the temperature zone 1 is 3-18 s, preferably 5-8 s, and more preferably 6 s.
Further, the residence time of the temperature zone 3 is 2-15 s, preferably 4-6 s, and more preferably 4.8 s.
Further, the residence time of the temperature zone 4 is 1-12 s, preferably 3-4 s, and more preferably 3.5 s.
In the calculation of the total reaction time, the total reaction time is the sum of the residence times of the temperature zones 1, 3 and 4, and the residence time of the temperature zone 2 is not taken into account. The reason is that the material does not react in the temperature zone 2 and only plays a role in controlling the temperature of the material. In a particular embodiment, to simplify the operation of temperature control, modules of microreactors are also used, but the skilled person will know that many alternatives can be used to achieve the same effect, for example a vessel in which the temperature can be controlled.
The process of the continuous flow preparation method of the invention is as follows:
continuously adding reaction raw materials of 2, 6-diethyl-4-methylaniline, diazotization reagent, acid and bromination reagent into the feed inlet of the integrated reactor.
In the case of diazotisation by continuous flow, the prior art such as org. process res. dev.,2018,22(12), pp 1828-1834 generally mixes the aromatic amine with the acid before reacting with the diazotising agent. However, through screening tests of a continuous flow reaction mixing mode, the aniline 2, 6-diethyl-4-methylaniline with a specific structure has low solubility of the generated salt in an aqueous phase when being mixed with acid, so that the whole continuous flow reaction efficiency is relatively low.
If the 2, 6-diethyl-4-methylaniline and the diazotization reagent are mixed firstly, the mixture is easily separated into two phases and is inconvenient to feed.
Thus, it is preferred to first mix the diazotizing agent with the acid and then perform the diazotization reaction with 2, 6-diethyl-4-methylaniline to produce the corresponding diazonium salt. When the diazotizing agent is mixed with an acid, a reaction occurs to generate the corresponding nitrous acid or nitrosyl group, depending on the difference between the diazotizing agent and the acid used. Such reactions are generally exothermic and are advantageously carried out by the endothermic pre-cooling of the thermal control fluid in the reaction apparatus. Control of the residence time of the mixing reaction of this step is relatively unimportant and does not require necessarily complete reaction over the course of the continuous flow reaction of the present invention relative to the subsequent diazotization and bromination reactions.
The diazotizing agent is selected from nitrite or nitrososulfate. The nitrite is selected from lithium nitrite, sodium nitrite, potassium nitrite, ammonium nitrite, magnesium nitrite, barium nitrite or calcium nitrite, and preferably the sodium nitrite with lower cost.
The concentration of the feed liquid of the diazotization reagent is 10 wt% -95 wt%, and when the diazotization reagent is sodium nitrite, the concentration of the feed liquid is preferably 20 wt% -30 wt%, and more preferably 25 wt%. When the concentration is lower, the content of the phenolic by-products is increased; at higher concentrations, some of the diazonium salt will precipitate, which is detrimental to the overall continuous flow reaction.
The feed liquid of the diazotization reagent is selected from liquid diazotization reagent, diazotization reagent slurry liquid, diazotization reagent suspension, emulsion and solution, preferably aqueous solution, and is beneficial to the dissolution of subsequent diazonium salt, thereby being beneficial to the whole continuous flow reaction.
Since the subsequent reaction to diazotization is a bromination reaction, hydrobromic acid is preferred to reduce the introduction of new species of impurities. The concentration of the hydrobromic acid is preferably 48 wt%. It was found that by reducing the concentration of hydrobromic acid, the content of phenolic by-products increased.
In a preferred embodiment, the nitrous acid is prepared in situ by mixing hydrobromic acid with sodium nitrite. The reaction temperature for preparing the nitrous acid is-15-25 ℃. The reaction is usually exothermic and the reaction temperature is controlled endothermically by the thermal control fluid of the reaction apparatus. If the temperature is too low, the energy consumption is high; if the temperature is too high, nitrous acid is easily decomposed, thereby reducing the yield of the entire continuous flow reaction. Tests show that the effect difference is not large when the temperature is 0-15 ℃, so that the temperature is preferably 0-15 ℃.
The temperature of the diazotization reaction is-15-25 ℃. Since the diazotization process is exothermic, the temperature of the thermal control fluid is slightly below the temperature required for the reaction, thereby removing excess heat from the reaction mixture. If the temperature is too low, the energy consumption is high, the generated diazonium salt is easy to separate out and is not beneficial to the reaction, and particularly when the used reaction device is a microreactor, the blockage of a reaction module can be caused; if the temperature is too high, the diazonium salt is easily decomposed, thereby reducing the yield of the entire continuous flow reaction. Tests show that the effect difference is not large when the temperature is 0-15 ℃, so that the temperature is preferably 0-15 ℃. Multiple batches of verification prove that the diazonium salt generated by the subsequent diazotization reaction at the temperature of 5 ℃ is stable, the reaction stability among batches is higher, and the preferable temperature is 5 ℃.
In a preferred embodiment, the temperature of the mixture of the diazotizing agent and the acid is the same as the temperature of the next diazotization reaction, so that the temperature control effect of the diazotization reaction is better.
The temperature of the bromination reaction is 0-90 ℃, preferably 45-80 ℃, and more preferably 80 ℃. Since the bromination reaction is exothermic, higher temperatures are required for initiation, and the actual internal reaction temperature is higher. The higher temperature is beneficial to improving the reaction selectivity, but tar is generated when the reaction is too high; too low a temperature increases the content of phenolic by-products.
The molar ratio of the 2, 6-diethyl-4-methylaniline to the diazotization reagent is 1: 1-10, preferably 1: 1-2, and more preferably 1: 1.6-1.7. When sodium nitrite is used as a diazotization reagent, the reaction effect is better when the dosage of the sodium nitrite is between 1.6 and 1.7eq, and if the dosage is less than 1.6eq, the raw material conversion is incomplete; if the amount is more than 1.7eq, the content of impurities and tar increases, and the purity of the final product decreases.
The molar ratio of the 2, 6-diethyl-4-methylaniline to the acid is 1: 1-10, preferably 1: 1-3, and more preferably 1: 2. When the acid dosage is less than 2eq, the raw material conversion is incomplete; when the acid amount is more than 2eq, the content of by-products increases and the content of tar increases.
In combination with the integrated reaction described above as a preferred embodiment, the continuous flow synthesis process is carried out in an integrated reactor comprising 4 temperature zones, comprising the steps of:
(a) mixing and reacting the first material and the second material through a temperature zone 1, and pre-controlling the temperature of the third material in the temperature zone 2 or flowing through the temperature zone 2;
(b) mixing the material flowing through the temperature zone 1 and the material with the temperature pre-controlled by the temperature zone 2 in the temperature zone 3, flowing through the temperature zone 3, and completing diazotization reaction in the temperature zone to generate diazonium salt;
(c) and mixing the generated diazonium salt with a fourth material in a temperature zone 4, and allowing the mixture to flow through the temperature zone 4 to complete bromination reaction to obtain 2, 6-diethyl-4-methyl bromobenzene.
The 2, 6-diethyl-4-methyl bromobenzene obtained by the invention is a crude product, and can be further separated and purified by post-treatment. For example, after the bromination reaction is finished, methylcyclohexane is added to extract and separate phases, the upper organic phase is respectively washed by water, washed by saturated sodium carbonate and desolventized under reduced pressure to obtain crude products, the crude products are subjected to reduced pressure distillation (10mmHg) by an oil pump, and fractions at 80-90 ℃ are collected to obtain high-purity 2, 6-diethyl-4-methyl bromobenzene.
The invention has the beneficial effects that:
(1) the production is safe and efficient, and no diazonium salt is accumulated.
(2) Simple operation and high production efficiency.
(3) Solves the problem of high system viscosity in the kettle type reaction.
(4) The product yield and purity are high.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Drawings
FIG. 1 is a schematic reaction scheme of example 1 of the present invention.
FIG. 2 is a schematic reaction scheme of example 2 of the present invention.
Detailed Description
In the following specific embodiments, purity is HPLC purity and residence time is in modules. The reaction device adopted is a corning microchannel G1 glass reactor.
Example 1
As shown in FIG. 1, 48 wt% aqueous HBr and 25 wt% NaNO were taken 2 And introducing the aqueous solution into a precooling module at the flow rates of 37g/min and 52g/min respectively for mixing and precooling at the temperature of 5 ℃, and keeping the aqueous solution for 7.3 s. And introducing the 2, 6-diethyl-4-methylaniline into another precooling module at the flow rate of 18g/min for precooling at the temperature of 5 ℃ for 26.6 s. The pressure of the microreactor was 0.6 MPa.
Introducing the precooled material into the next module for mixing and reacting at 5 ℃ to generate a diazonium salt intermediate, wherein the retention time is 5.7 s.
The generated diazonium salt intermediate is continuously introduced into the next bromination module, and simultaneously 0.5eq FeSO is added 4 .7H 2 2eq 48% HBr 1eq NaBr solution and 64g/min speed is introduced into the bromination reaction moldIn the block, the bromination reaction was completed at 80 ℃ with a residence time of 4 s.
The total reaction residence time for the entire continuous flow reaction was 17 s.
After the bromination reaction is finished, methylcyclohexane is added for extraction and phase separation, and the upper organic phase is respectively washed by water, washed by saturated sodium carbonate and desolventized under reduced pressure to obtain the 2, 6-diethyl-4-methyl bromobenzene with the yield of 94 percent and the purity of 90 percent.
Example 2
As shown in FIG. 2, 48 wt% aqueous HBr and 48 wt% NaNO were taken 2 Introducing NaBr (1.7eq:2eq) aqueous solution into a precooling module at the flow rates of 41.3g/min and 82.6g/min respectively for mixing and precooling at the temperature of 5 ℃ for 6.0 s. And introducing another 2, 6-diethyl-4-methylaniline into another precooling module at the flow rate of 20g/min for precooling at the temperature of 5 ℃ for 24 s. The pressure of the microreactor was 0.9 MPa.
Introducing the precooled material into the next module for mixing and reacting at 5 ℃ to generate a diazonium salt intermediate, wherein the retention time is 4.8 s.
The generated diazonium salt intermediate is continuously introduced into the next bromination module, and simultaneously 0.5eq FeSO is added 4 .7H 2 O2 eq 48% HBr and the bromination solution was fed into the bromination module at a rate of 58.2g/min to complete the bromination reaction at 80 ℃ for 3.5 s.
The total reaction residence time for the entire continuous flow reaction was 14.3 s.
After the bromination reaction is finished, methylcyclohexane is added for extraction and phase separation, and the upper organic phase is respectively washed by water, washed by saturated sodium carbonate and desolventized under reduced pressure to obtain the 2, 6-diethyl-4-methyl bromobenzene with the yield of 92 percent and the purity of 96 percent.
Comparative example kettle reaction
Firstly, dropwise adding 2, 6-diethyl-4-methylaniline (1eq) into a 48 wt% hydrobromic acid (3eq) aqueous solution, fully reacting at 70-80 ℃ to form salt, gradually increasing the viscosity of the system in the salt forming process, and ensuring that the solid content of the system reaches 40% after dropwise adding, and the fluidity is poor. Then the temperature of the system is reduced from about 80 ℃ to-10 to-15 ℃, a large amount of aniline salt is separated out from the system, the viscosity is further increased to form paste, and then 25 wt% of sodium nitrite aqueous solution (1.1eq) is slowly dripped to carry out diazotization reaction. And mixing, stirring and heating 1eq 48 wt% of hydrobromic acid, 0.5eq ferrous sulfate heptahydrate and 3eq sodium bromide to 80 ℃ to prepare a bromination reagent, dropwise adding the diazotization reaction prepared in the previous step into the bromination reagent to complete bromination reaction, keeping the temperature of 70-80 ℃ in the dropwise adding process, and stirring and reacting for 30min after the dropwise adding is completed. Then, adding methylcyclohexane for extraction and phase separation, and carrying out vacuum distillation on the upper layer of organic phase to recover the solvent, wherein the yield of the product is 85 percent, and the purity is 92 percent.
Claims (34)
1. A continuous flow preparation method of 2, 6-diethyl-4-methyl bromobenzene is characterized in that the method is carried out in an integrated reactor, a first material, a second material, a third material and a fourth material are continuously added into a feed inlet of the integrated reactor, diazotization and bromination reactions are sequentially carried out, and 2, 6-diethyl-4-methyl bromobenzene is continuously obtained from a discharge outlet of the integrated reactor;
the first material contains a diazotization reagent, the second material contains an acid, the third material contains 2, 6-diethyl-4-methylaniline, and the fourth material contains a bromination reagent;
wherein the molar ratio of the 2, 6-diethyl-4-methylaniline to the diazotization reagent is 1: 1-2;
the molar ratio of the 2, 6-diethyl-4-methylaniline to the acid is 1: 1-3;
the molar ratio of the 2, 6-diethyl-4-methylaniline to the bromine element in the total using amount of the brominating reagent is 1: 2-6;
the process is carried out in an integrated reactor comprising 4 temperature zones, comprising the steps of:
(a) the first material and the second material are mixed and reacted through a temperature zone 1, and the third material is pre-controlled in the temperature zone 2 or flows through the temperature zone 2;
(b) mixing the material flowing through the temperature zone 1 and the material with the temperature pre-controlled by the temperature zone 2 in the temperature zone 3, flowing through the temperature zone 3, and completing diazotization reaction in the temperature zone to generate diazonium salt;
(c) mixing the generated diazonium salt with a fourth material in a temperature zone 4, allowing the mixture to flow through the temperature zone 4, and completing bromination reaction in the mixture to obtain 2, 6-diethyl-4-methyl bromobenzene;
the temperature of the temperature zone 1 is 0-15 ℃; the temperature of the temperature zone 2 is 0-15 ℃; the temperature of the temperature zone 3 is 0-15 ℃; the temperature of the temperature zone 4 is 45-80 ℃; and
the total reaction time is 0.1 min-54 s.
2. The continuous flow process of claim 1, wherein the integrated reactor is a modular structure comprising a plurality of temperature zones, each temperature zone independently comprises more than one reactor module or reactor module group, the reactor module group comprises a plurality of reactor modules connected in series or in parallel, and the temperature zones are connected with each other.
3. The continuous-flow production process according to claim 1 or 2, wherein the integrated reactor is a continuous-flow microreactor.
4. The continuous-flow preparation process of claim 3, wherein the continuous-flow microreactor comprises at least three sequentially connected individual fluidic modules and the continuous-flow microreactor has a microreactor total volume of from 25mL to 2250 mL.
5. The continuous-flow production process of claim 3, wherein the continuous-flow microreactor comprises three to fifteen serially connected individual fluidic modules.
6. The continuous-flow production process of claim 1 or 2, wherein the total reaction time is 7-18 s.
7. The continuous-flow production process according to claim 1 or 2, wherein the total reaction time is 14-15 s.
8. The continuous-flow production process of claim 4, wherein the tortuous fluid flow passages in each individual fluidic module comprise a plurality of bends having bend angles of 90 ° to 180 °.
9. The continuous-flow production process of claim 4, wherein the continuous channel in each individual fluidic module has a continuous channel depth of from 0.8-3 mm; the continuous channel in each individual fluidic module has a continuous channel width of from 0.7 to 1.1 mm.
10. The continuous-flow production process of claim 4, wherein the continuous channel in each individual fluidic module comprises a plurality of continuous mixing chambers, each continuous mixing chamber comprising at least one flow splitting structure, each continuous mixing chamber having a chamber width greater than the continuous channel width.
11. The continuous-flow production process of claim 10, wherein the chamber width of each continuous mixing chamber is 1-20 mm.
12. The continuous-flow production process of claim 10, wherein each continuous mixing chamber has a chamber width of 3-15 mm.
13. A continuous flow process according to claim 1 or 2 wherein the diazotising agent is first mixed with an acid, the reaction is complete or incomplete and the resulting material is then diazotised with 2, 6-diethyl-4-methylaniline to form the corresponding diazonium salt.
14. The continuous-flow production process according to claim 1 or 2, wherein the diazotizing agent is selected from nitrite or nitrosylsulfuric acid; the nitrite is selected from lithium nitrite, sodium nitrite, potassium nitrite, ammonium nitrite, magnesium nitrite, barium nitrite or calcium nitrite.
15. The continuous-flow production process of claim 14, wherein the nitrite is sodium nitrite.
16. The continuous-flow production process according to claim 1 or 2, wherein the feed solution concentration of the diazotizing agent is 10 wt% to 95 wt%.
17. The continuous-flow production process of claim 15, wherein the feed solution concentration of sodium nitrite is between 20 wt% and 30 wt%.
18. The continuous-flow production process of claim 15, wherein the feed solution concentration of nitrite is 25 wt%.
19. The continuous-flow production process according to claim 1 or 2, wherein the acid is selected from hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, nitric acid or oxalic acid.
20. The continuous-flow production process of claim 1 or 2, wherein the acid is hydrobromic acid.
21. The continuous-flow production process of claim 20, wherein the concentration of hydrobromic acid is 48 wt%.
22. The continuous-flow production process according to claim 1 or 2, wherein the brominating reagent is selected from hydrobromic acid and/or metal bromides;
the fourth material also contains cuprous salt, ferric salt or ferrous salt.
23. The continuous-flow production process of claim 22, wherein the metal bromide is sodium bromide or potassium bromide.
24. The continuous-flow production process of claim 1 or 2, wherein the fourth material further comprises ferrous sulfate.
25. The continuous-flow production process of claim 1 or 2, wherein the first material further comprises a metal bromide.
26. The continuous-flow production process according to claim 1 or 2, characterized in that: the molar ratio of the 2, 6-diethyl-4-methylaniline to the diazotization reagent is 1: 1.6-1.7;
the molar ratio of the 2, 6-diethyl-4-methylaniline to the acid is 1: 2;
the molar ratio of the 2, 6-diethyl-4-methylaniline to the bromine element in the total using amount of the brominating reagent is 1: 4.
27. The continuous-flow production process according to claim 1 or 2, wherein the temperature zone 1 is at a temperature of 5 ℃; the temperature of the temperature zone 2 is 5 ℃; the temperature of the temperature zone 3 is 5 ℃; the temperature of the warm zone 4 is 80 ℃.
28. The continuous-flow production process of claim 27, wherein the residence time of the temperature zone 1 is 3-18 s; the residence time of the temperature zone 3 is 2-15 s; the residence time of the temperature zone 4 is 1-12 s.
29. The continuous-flow production process of claim 28, wherein the residence time of the temperature zone 1 is 5-8 s.
30. The continuous-flow production process of claim 28, wherein the temperature zone 1 has a residence time of 6 s.
31. The continuous-flow production process of claim 28 or 29, wherein the residence time of the temperature zone 3 is 4-6 s.
32. The continuous-flow production process according to claim 28 or 29, wherein the residence time of the temperature zone 3 is 4.8 s.
33. The continuous-flow production process of claim 28 or 29, wherein the residence time of the temperature zone 4 is 3-4 s.
34. The continuous-flow production process according to claim 28 or 29, wherein the residence time of the temperature zone 4 is 3.5 s.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102395546A (en) * | 2009-03-12 | 2012-03-28 | 拜耳作物科学公司 | Method for producing aromatic chlorine and bromine compounds |
| CN105693549A (en) * | 2016-01-25 | 2016-06-22 | 南京工业大学 | Method for preparing diazonium salt by utilizing micro-reactor |
| CN109651068A (en) * | 2018-12-12 | 2019-04-19 | 江苏中旗科技股份有限公司 | The synthetic method of pinoxaden intermediate (2,6- diethyl -4- methyl) phenylacetic acid |
-
2019
- 2019-06-19 CN CN201910530204.9A patent/CN110117216B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102395546A (en) * | 2009-03-12 | 2012-03-28 | 拜耳作物科学公司 | Method for producing aromatic chlorine and bromine compounds |
| CN105693549A (en) * | 2016-01-25 | 2016-06-22 | 南京工业大学 | Method for preparing diazonium salt by utilizing micro-reactor |
| CN109651068A (en) * | 2018-12-12 | 2019-04-19 | 江苏中旗科技股份有限公司 | The synthetic method of pinoxaden intermediate (2,6- diethyl -4- methyl) phenylacetic acid |
Non-Patent Citations (3)
| Title |
|---|
| Continuous-Flow Diazotization for Efficient Synthesis of Methyl 2-(Chlorosulfonyl)benzoate: An Example of Inhibiting Parallel Side Reactions;Zhiqun Yu et al.;《Organic Process Research & Development》;20161117;第20卷(第12期);第2116-2123页 * |
| Continuous-flow generation of anhydrous diazonium species: Monolithic microfluidic reactors for the chemistry of unstable intermediates;Robin Fortt et al.;《Organic Process Research & Development》;20030531;第7卷(第5期);第762-768页 * |
| 连续流反应技术开发及其在制药危险工艺中的应用;苏为科等;《中国医药工业杂志》;20171231;第48卷(第4期);第469-482页 * |
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