CN110156560B - Method for preparing 2, 6-diethyl-4-methyl bromobenzene - Google Patents
Method for preparing 2, 6-diethyl-4-methyl bromobenzene Download PDFInfo
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Abstract
The invention discloses a continuous flow preparation method of 2, 6-diethyl-4-methyl bromobenzene, the whole preparation process is carried out in an integrated reactor, nitrite reagent, alcohol and acid are continuously added into a feed inlet of the integrated reactor to prepare nitrite ester, diazotization reaction is carried out on the nitrite ester and 2, 6-diethyl-4-methyl aniline, bromination reaction is carried out on the obtained diazonium salt and bromination reagent, and 2, 6-diethyl-4-methyl bromobenzene is continuously obtained at a discharge outlet of the integrated reactor. 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 is accumulated in the reaction kettle, and the diazonium salt is easy to decompose to cause 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 method for preparing 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, the method comprises the steps of carrying out nitrite preparation reaction, diazotization reaction and bromination reaction in sequence, and 2, 6-diethyl-4-methyl bromobenzene is continuously obtained at a discharge outlet of the integrated reactor; the first material contains nitrite, the second material contains acid and alcohol, the third material contains 2, 6-diethyl-4-methylaniline, and the fourth material contains brominating reagent.
It was found that when nitrite and acid are mixed in the same material, the final product yield decreases. When nitrite is mixed with alcohol in the same material, the final yield is also reduced.
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 90-180 degrees.
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 which are connected in sequence, and the total volume of the continuous-flow microreactor is 25-2250 mL.
The total reaction time of the method is 0.1-60 min.
In a specific embodiment of the present 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 3-50 s, preferably 5-20 s, and more preferably 5-15 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 first material and the second material are mixed, the reaction is complete or incomplete, the obtained material and the third material are subjected to diazotization reaction to generate corresponding diazonium salt, and the diazonium salt and the fourth material are subjected to bromination reaction to obtain the 2, 6-diethyl-4-methyl bromobenzene.
Further, the nitrite is selected from lithium nitrite, sodium nitrite, potassium nitrite, magnesium nitrite, barium nitrite or calcium nitrite, preferably sodium nitrite.
Further, the concentration of the nitrite solution is 10 wt% -95 wt%; when the nitrite is sodium nitrite, the concentration of the feed liquid is preferably 20 wt% -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 alcohol is selected from C 1 -C 8 Alcohols, preferably methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, tert-butanol, pentanol or isopentanol.
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 molar ratio of the 2, 6-diethyl-4-methylaniline to the alcohol is 1: 1-10, preferably 1: 1-3, and more preferably 1: 2.5.
The molar ratio of the alcohol to the acid is 1: 1-5, preferably 1: 1-3, and more preferably 1: 1.5.
The molar ratio of the 2, 6-diethyl-4-methylaniline to the nitrite is 1: 1-10, preferably 1: 2-5, and more preferably 1: 3.75.
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. Actual amount of bromination
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 flowing through the temperature zone 2 in the temperature zone 3, and allowing the mixture to flow through the temperature zone 3, thereby completing diazotization reaction 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 the 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 35-85 ℃, and more preferably 45 ℃.
Further, the residence time of the temperature zone 1 is 3-18 s, preferably 3-8 s, and more preferably 3.2 s.
Further, the residence time of the temperature zone 3 is 2-15 s, preferably 2-6 s, and more preferably 2.3 s.
Further, the residence time of the temperature zone 4 is 1-12 s, preferably 1-4 s, and more preferably 1.2 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 alcohol, acid, nitrite, 2, 6-diethyl-4-methylaniline and brominating reagent into the feed inlet of the integrated reactor.
The nitrite is selected from lithium nitrite, sodium nitrite, potassium nitrite, magnesium nitrite, barium nitrite or calcium nitrite, and preferably is sodium nitrite with low cost and high stability.
The concentration of the nitrite in the feed liquid is 10 wt% -95 wt%, and when the nitrite 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 nitrite feed liquid is selected from liquid nitrite reagent, nitrite reagent slurry liquid, nitrite reagent suspension, emulsion and solution, preferably aqueous solution, and is beneficial to dissolving 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.
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, the reaction is not facilitated, 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 shows that when the temperature is lower than 5 ℃, the diazonium salt generated by the subsequent diazotization reaction is stable, and the reaction stability between batches is higher, and more preferably 5 ℃.
The temperature of the bromination reaction is 0-90 ℃, preferably 35-85 ℃, and more preferably 45 ℃. 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 alcohol is 1: 1-10, preferably 1: 1-3, and more preferably 1: 2.5. The molar ratio of the alcohol to the acid is 1: 1-5, preferably 1: 1-3, and more preferably 1: 1.5. When the acid dosage is less than 1eq, the raw material conversion is incomplete; when the acid amount is more than 1.5eq, the content of by-products increases and the content of tar increases. The conversion is incomplete when the alcohol is small, and the pressure of the reaction system is increased when the alcohol is large.
The molar ratio of the 2, 6-diethyl-4-methylaniline to the nitrite is 1: 1-10, preferably 1: 2-5, and more preferably 1: 3.75. If the salt content is high, the precipitation and blockage are caused, and if the salt content is low, the conversion is incomplete. When the nitrite is sodium nitrite, the reaction effect is better when the dosage of the sodium nitrite is between 1.5 and 4eq, and if the dosage is less than 1.5eq, the conversion of the raw material is incomplete; if the amount is more than 4eq, the content of impurities and tar increases, and the purity of the final product decreases.
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 flowing through the temperature zone 2 with the temperature pre-controlled temperature in the temperature zone 3, and flowing through the temperature zone 3 to complete diazotization reaction therein 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, the effluent product is connected into a collecting tank with a cooling water cooling device, and the first is addedExtracting with cyclohexane, separating phases, and subjecting the organic phase to saturated NaHCO 3 Washing with water solution, washing with water, and distilling under reduced pressure to obtain high-purity 2, 6-diethyl-4-methylbromobenzene.
The invention has the beneficial effects that:
(1) the production process is intrinsically safe, and the high-risk diazonium salt is consumed as soon as being generated, so that the diazonium salt is not 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 an embodiment of the present invention.
Detailed Description
In the following specific embodiments, purity is HPLC purity and residence time is in modules. The reaction apparatus used was a corning microchannel G1 glass reactor, the reaction volume of each module being 8.5 mL.
As shown in fig. 1, the process flow scheme adopted by the present invention is as described above, and comprises 4 microchannel reactor modules connected in series and a collection tank with a cooling water cooling device, wherein raw materials of isoamyl alcohol, an aqueous hydrobromic acid solution and an aqueous sodium nitrite solution are pumped from a first module, isoamyl nitrite is prepared in situ through the reaction of the first module and a second module, raw material of 2, 6-diethyl-4-methylaniline is pumped into the other inlet of a third module connected in series, generated diazonium salt is subjected to bromination reaction in a fourth module, and finally, the diazonium salt flows out from an outlet and enters the collection tank. And the outsides of the first module, the second module, the third module and the fourth module are respectively provided with an external heat exchanger which is convenient for adjusting and controlling the reaction temperature, and heat exchange media of the external heat exchangers are heat-conducting silicone oil.
Example 1
Preparation work: the microchannel continuous flow reactor is assembled as shown in fig. 1, and ferrous sulfate heptahydrate, sodium bromide and hydrobromic acid are mixed according to the molar ratio of 0.2:1.5:1.7 to obtain a uniformly mixed solution.
The operation work of the micro-channel continuous flow reactor is as follows: setting flow parameters of the pumps and temperature parameters of the temperature zones to enable the molar ratio of 2, 6-diethyl-4-methylaniline, isoamyl alcohol, hydrobromic acid and 25 wt% of sodium nitrite to be 1:1.5:1.65:1.8, controlling the mass flow of isoamyl alcohol to be 20g/min, the mass flow of hydrobromic acid to be 42g/min, the mass flow of 25 wt% of sodium nitrite water solution to be 75g/min, controlling the reaction temperature of the first module and the second module to be 0 ℃, pumping in 2, 6-diethyl-4-methylaniline, controlling the mass flow to be 24.7g/min, controlling the reaction temperature of the third module to be 5 ℃, controlling the mass flow of a mixed solution of ferrous sulfate heptahydrate, sodium bromide and hydrobromic acid to be 75g/min, controlling the reaction temperature of the fourth module to be 85 ℃ and controlling the pressure to be 0.4 MPa.
The residence time of the first module was 6.2 s.
The residence time of the third module was 4.6 s.
The residence time of the fourth module was 3.1 s.
In the reaction, the molar ratio of the 2, 6-diethyl-4-methylaniline, the ferrous sulfate heptahydrate, the sodium bromide and the hydrobromic acid is 1:0.2:1.5: 1.7.
The total reaction residence time for the entire continuous flow reaction was 13.9 s.
And (3) post-reaction treatment: the effluent product is put into a collecting tank with a cooling water cooling device, methylcyclohexane is added for extraction, phase separation is carried out, and the organic phase is subjected to saturated NaHCO 3 Washing with water solution, washing with water, and distilling under reduced pressure to obtain 2, 6-diethyl-4-methylbromobenzene with purity of 95% and yield of 86%.
Example 2
Preparation: a micro-channel continuous flow reactor is assembled as shown in figure 1, ferrous sulfate heptahydrate, sodium bromide and hydrobromic acid are prepared according to the molar ratio of 0.2:2.0:2.0 (taking 2, 6-diethyl-4-methylaniline as 1), and a uniformly mixed solution is obtained.
The operation work of the micro-channel continuous flow reactor is as follows: setting flow parameters of the pumps and temperature parameters of the temperature zones so that the molar ratio of 2, 6-diethyl-4-methylaniline, isoamyl alcohol, hydrobromic acid and 25 wt% of sodium nitrite is 1:1.5:1.8:1.8, controlling the mass flow of isoamyl alcohol to be 30g/min, the mass flow of hydrobromic acid to be 68.8g/min, the mass flow of 25 wt% of sodium nitrite water solution to be 112.7g/min, the reaction temperature of the first module and the second module to be 0 ℃, pumping in 2, 6-diethyl-4-methylaniline, controlling the mass flow to be 37g/min, the reaction temperature of the third module to be 5 ℃, the mass flow of the mixed solution of ferrous sulfate heptahydrate, sodium bromide and hydrobromic acid to be 136g/min, and the reaction temperature of the fourth module to be 85 ℃ and the pressure to be 0.8 MPa.
The residence time of the first module was 3.4 s.
The residence time of the third module was 2.3 s.
The residence time of the fourth module was 1.7 s.
In the reaction, the molar ratio of the 2, 6-diethyl-4-methylaniline, the ferrous sulfate heptahydrate, the sodium bromide and the hydrobromic acid is 1:0.2:2.0: 2.0.
The total reaction residence time for the entire continuous flow reaction was 7.4 s.
And (3) post-reaction treatment: the effluent product is put into a collecting tank with a cooling water cooling device, methylcyclohexane is added for extraction, phase separation is carried out, and the organic phase is subjected to saturated NaHCO 3 Washing with water solution, washing with water, and distilling under reduced pressure to obtain 2, 6-diethyl-4-methylbromobenzene with purity of 97% and yield of 80%.
Example 3
Preparation work: the microchannel continuous flow reactor is assembled as shown in fig. 1, and ferrous sulfate heptahydrate, sodium bromide and hydrobromic acid are mixed according to the molar ratio of 0.2:2.0:2.0 to obtain a uniformly mixed solution.
The operation work of the micro-channel continuous flow reactor is as follows: setting flow parameters of the pumps and temperature parameters of the temperature zones so that the molar ratio of 2, 6-diethyl-4-methylaniline, isoamyl alcohol, hydrobromic acid and 25 wt% of sodium nitrite is 1:2.5:3.75:3.75, controlling the mass flow of isoamyl alcohol to be 30g/min, the mass flow of hydrobromic acid to be 86g/min, the mass flow of 25 wt% of sodium nitrite aqueous solution to be 140.8g/min, the reaction temperature of the first module and the second module to be 5 ℃, pumping in 2, 6-diethyl-4-methylaniline, controlling the mass flow to be 22.2g/min, the reaction temperature of the third module to be 5 ℃, the mass flow of mixed solution of ferrous sulfate heptahydrate, sodium bromide and hydrobromic acid to be 82g/min, and the reaction temperature of the fourth module to be 45 ℃ and the pressure to be 0.6 MPa. The molar ratio of the 2, 6-diethyl-4-methylaniline to the bromine element in the total using amount of the brominating agent is
The residence time of the first module was 3.2 s.
The residence time of the third module was 2.3 s.
The residence time of the fourth module was 1.2 s.
In the reaction, the molar ratio of the 2, 6-diethyl-4-methylaniline, the ferrous sulfate heptahydrate, the sodium bromide and the hydrobromic acid is 1:0.2:2.0: 2.0.
The total reaction residence time for the entire continuous flow reaction was 6.7 s.
And (3) post-reaction treatment: the effluent product is put into a collecting tank with a cooling water cooling device, methylcyclohexane is added for extraction, phase separation is carried out, and the organic phase is subjected to saturated NaHCO 3 Washing with water solution, washing with water, and distilling under reduced pressure to obtain 2, 6-diethyl-4-methylbromobenzene with purity of 98% and yield of 93%.
Example 4
Preparation work: a micro-channel continuous flow reactor is assembled as shown in fig. 1, and ferrous sulfate heptahydrate, sodium bromide and hydrobromic acid are mixed according to a molar ratio of 0.2:0:1.7 to obtain a uniformly mixed solution.
The operation work of the micro-channel continuous flow reactor is as follows: setting flow parameters of the pumps and temperature parameters of the temperature zones to enable the molar ratio of 2, 6-diethyl-4-methylaniline, isoamyl alcohol, hydrobromic acid and 25 wt% of sodium nitrite to be 1:1.5:1.65:1.8, controlling the mass flow of isoamyl alcohol to be 20g/min, the mass flow of hydrobromic acid to be 42g/min, the mass flow of 25 wt% of sodium nitrite water solution to be 75g/min, controlling the reaction temperature of the first module and the second module to be 0 ℃, pumping in 2, 6-diethyl-4-methylaniline, controlling the mass flow to be 24.7g/min, controlling the reaction temperature of the third module to be 5 ℃, controlling the mass flow of a mixed solution of ferrous sulfate heptahydrate, sodium bromide and hydrobromic acid to be 52g/min, and controlling the reaction temperature of the fourth module to be 85 ℃ and controlling the pressure to be 0.4 MPa. The molar ratio of the 2, 6-diethyl-4-methylaniline to the bromine element in the total using amount of the brominating agent is
The residence time of the first module was 6.2 s.
The residence time of the third module was 4.6 s.
The residence time of the fourth module was 3.1 s.
In the reaction, the molar ratio of the 2, 6-diethyl-4-methylaniline, the ferrous sulfate heptahydrate, the sodium bromide and the hydrobromic acid is 1:0.2:2.0: 1.7.
The total reaction residence time for the entire continuous flow reaction was 13.9 s.
And (3) post-reaction treatment: the effluent product is put into a collecting tank with a cooling water cooling device, methylcyclohexane is added for extraction, phase separation is carried out, and the organic phase is subjected to saturated NaHCO 3 Washing with water solution, washing with water, and distilling under reduced pressure to obtain 2, 6-diethyl-4-methylbromobenzene with purity of 71% and yield of 30%.
Example 5
Preparation work: the microchannel continuous flow reactor is assembled as shown in fig. 1, and ferrous sulfate heptahydrate, sodium bromide and hydrobromic acid are mixed according to the molar ratio of 0.2:2.0:2.0 to obtain a uniformly mixed solution.
The operation work of the micro-channel continuous flow reactor is as follows: setting flow parameters of the pumps and temperature parameters of the temperature zones so that the molar ratio of 2, 6-diethyl-4-methylaniline, isoamyl alcohol, hydrobromic acid and 25 wt% of sodium nitrite is 1:1.5:1.8:1.8, controlling the mass flow of isoamyl alcohol to be 30g/min, the mass flow of hydrobromic acid to be 68.8g/min, the mass flow of 25 wt% of sodium nitrite water solution to be 112.7g/min, the reaction temperature of the first module and the second module to be 0 ℃, pumping in 2, 6-diethyl-4-methylaniline, controlling the mass flow to be 37g/min, the reaction temperature of the third module to be 5 ℃, the mass flow of the mixed solution of ferrous sulfate heptahydrate, sodium bromide and hydrobromic acid to be 136g/min, and the reaction temperature of the fourth module to be 25 ℃ and the pressure to be 0.8 MPa. The molar ratio of the 2, 6-diethyl-4-methylaniline to the bromine element in the total using amount of the brominating agent is
The residence time of the first module was 3.4 s.
The residence time of the third module was 2.3 s.
The residence time of the fourth module was 1.7 s.
In the reaction, the molar ratio of the 2, 6-diethyl-4-methylaniline, the ferrous sulfate heptahydrate, the sodium bromide and the hydrobromic acid is 1:0.2:2.0: 2.0.
The total reaction residence time for the entire continuous flow reaction was 7.4 s.
And (3) post-reaction treatment: the effluent product is put into a collecting tank with a cooling water cooling device, methylcyclohexane is added for extraction, phase separation is carried out, and the organic phase is subjected to saturated NaHCO 3 Washing with water solution, washing with water, and distilling under reduced pressure to obtain 2, 6-diethyl-4-methylbromobenzene with purity of 81% and yield of 62%.
Example 6
Preparation work: the microchannel continuous flow reactor is assembled as shown in fig. 1, and ferrous sulfate heptahydrate, sodium bromide and hydrobromic acid are mixed according to the molar ratio of 0.2:2.0:2.0 to obtain a uniformly mixed solution.
The operation work of the micro-channel continuous flow reactor is as follows: setting flow parameters of the pumps and temperature parameters of the temperature zones so that the molar ratio of 2, 6-diethyl-4-methylaniline, isoamyl alcohol, hydrobromic acid and 25 wt% of sodium nitrite is 1:2.5:3.75:3.75, controlling the mass flow of isoamyl alcohol to be 30g/min, the mass flow of hydrobromic acid to be 86g/min, the mass flow of 25 wt% of sodium nitrite aqueous solution to be 140.8g/min, controlling the reaction temperature of the first module and the second module to be 25 ℃, pumping in 2, 6-diethyl-4-methylaniline, controlling the mass flow to be 22.2g/min, controlling the reaction temperature of the third module to be 25 ℃, controlling the mass flow of the mixed solution of ferrous sulfate heptahydrate, sodium bromide and hydrobromic acid to be 82g/min, controlling the reaction temperature of the fourth module to be 45 ℃ and controlling the pressure to be 0.6 MPa. The molar ratio of the 2, 6-diethyl-4-methylaniline to the bromine element in the total using amount of the brominating agent is
The residence time of the first module was 3.2 s.
The residence time of the third module was 2.3 s.
The residence time of the fourth module was 1.2 s.
In the reaction, the molar ratio of the 2, 6-diethyl-4-methylaniline, the ferrous sulfate heptahydrate, the sodium bromide and the hydrobromic acid is 1:0.2:2.0: 2.0.
The total reaction residence time for the entire continuous flow reaction was 6.7 s.
And (3) post-reaction treatment: the effluent product is put into a collecting tank with a cooling water cooling device, methylcyclohexane is added for extraction, phase separation is carried out, and the organic phase is subjected to saturated NaHCO 3 Washing with water solution, washing with water, and distilling under reduced pressure to obtain 2, 6-diethyl-4-methylbromobenzene with purity of 79% and yield of 53%.
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 ℃, at the moment, a large amount of aniline salt is precipitated in the system, the viscosity is further increased to be pasty, and then 25% sodium nitrite aqueous solution (1.1eq) is slowly dripped to carry out diazotization reaction. And mixing, stirring and heating 1eq 48% 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 dropwise adding. 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 (35)
1. The method for preparing 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, the method comprises the sequential nitrite preparation reaction, diazotization reaction and bromination reaction, and 2, 6-diethyl-4-methyl bromobenzene is continuously obtained from a discharge outlet of the integrated reactor;
the first material contains nitrite, the second material contains acid and alcohol, the third material contains 2, 6-diethyl-4-methylaniline, and the fourth material contains brominating reagent;
wherein the molar ratio of the 2, 6-diethyl-4-methylaniline to the alcohol is 1: 1-3;
the molar ratio of the alcohol to the acid is 1: 1-3;
the molar ratio of the 2, 6-diethyl-4-methylaniline to the nitrite is 1: 2-5;
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) 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 flowing through the temperature zone 2 with the temperature pre-controlled temperature in the temperature zone 3, and flowing through the temperature zone 3 to complete diazotization reaction therein 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 35-85 ℃; and
the total reaction time is 3-50 s.
2. The method 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 is composed of a plurality of reactor modules connected in series or in parallel, and the temperature zones are connected with each other.
3. The process of claim 1 or 2, wherein the integrated reactor is a continuous-flow microreactor.
4. The method according to 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 25-2250 mL.
5. The method of claim 3, wherein the continuous-flow microreactor comprises three to fifteen serially connected individual fluidic modules.
6. The process according to claim 1 or 2, wherein the total time of the reaction is 5 to 40 s.
7. The process according to claim 1 or 2, wherein the total time of the reaction is 5 to 15 s.
8. The method of claim 4, wherein the tortuous fluid flow passages in each individual fluid module comprise a plurality of bends having a bend angle of 90-180 °.
9. The method of claim 4, wherein 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.
10. The method 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 method of claim 10, wherein the chamber width of each successive mixing chamber is 1-20 mm.
12. The method of claim 10, wherein the chamber width of each successive mixing chamber is 3-15 mm.
13. The process of claim 1 or 2, wherein the first material is mixed with the second material, the reaction is complete or incomplete, the resulting material is diazotized with 2, 6-diethyl-4-methylaniline to produce the corresponding diazonium salt, and the diazonium salt is reacted with a brominating reagent to produce 2, 6-diethyl-4-methylbromobenzene.
14. The method according to claim 1 or 2, wherein the nitrite is selected from the group consisting of lithium nitrite, sodium nitrite, potassium nitrite, magnesium nitrite, barium nitrite and calcium nitrite.
15. A method according to claim 1 or 2, wherein said nitrite is sodium nitrite.
16. The method according to claim 1 or 2, wherein the feed solution concentration of nitrite is 10 wt% to 95 wt%.
17. The method of claim 15, wherein the feed solution concentration of nitrite is 20 wt% to 30 wt%.
18. The method of claim 15, wherein the feed solution concentration of nitrite is 25 wt%.
19. The method according to claim 1 or 2, characterized in that the acid is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid or oxalic acid.
20. The process of claim 1 or 2, wherein the acid is hydrobromic acid.
21. The method of claim 20, wherein the concentration of hydrobromic acid is 48 wt%.
22. The process according to claim 1 or 2, characterized in that the alcohol is selected from C 1 -C 8 An alcohol.
23. The method according to claim 1 or 2, wherein the alcohol is selected from methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, tert-butanol, amyl alcohol or isoamyl alcohol.
24. The process according to claim 1 or 2, characterized in that the brominating reagent is selected from hydrobromic acid and/or metal bromides;
the fourth material also contains cuprous salt, ferric salt or ferrous salt.
25. A method according to claim 24 wherein the metal bromide is sodium bromide or potassium bromide.
26. The method of claim 24, wherein the ferrous salt is ferrous sulfate.
27. The process according to claim 1 or 2, characterized in that the molar ratio of 2, 6-diethyl-4-methylaniline to alcohol is 1: 2.5;
the molar ratio of the alcohol to the acid is 1: 1.5;
the molar ratio of the 2, 6-diethyl-4-methylaniline to the nitrite is 1: 3.75;
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.
28. The method according to claim 1 or 2, characterized in that the temperature of the temperature zone 1 is 5 ℃; the temperature of the temperature zone 2 is 5 ℃; the temperature of the temperature zone 3 is 5 ℃; the temperature of the temperature zone 4 is 45 ℃.
29. The method according to claim 28, wherein the residence time of the temperature zone 1 is 3 to 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.
30. The method according to claim 29, wherein the residence time of the temperature zone 1 is 3-8 s.
31. The method according to claim 29, characterized in that the residence time of the temperature zone 1 is 3.2 s.
32. The method according to claim 29 or 30, wherein the residence time of the temperature zone 3 is 2-6 s.
33. The method according to claim 29 or 30, characterized in that the residence time of the temperature zone 3 is 2.3 s.
34. The method according to claim 29 or 30, wherein the residence time of the temperature zone 4 is 1-4 s.
35. The method according to claim 29 or 30, characterized in that the residence time of the temperature zone 4 is 1.2 s.
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| CN105693549A (en) * | 2016-01-25 | 2016-06-22 | 南京工业大学 | Method for preparing diazonium salt by utilizing micro-reactor |
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