CN111018717A - Method for synthesizing 4-fluoro-2-nitroaniline by using microchannel reactor - Google Patents
Method for synthesizing 4-fluoro-2-nitroaniline by using microchannel reactor Download PDFInfo
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Abstract
The invention discloses a method for synthesizing 4-fluoro-2-nitroaniline by a microchannel reactor, which is characterized by comprising the following steps: adopting a corning high-flux continuous flow microchannel reactor, and mixing the p-fluoroacetanilide and the nitric acid in a molar ratio of 1: 1.0-1.5, respectively setting the flow rates of 20-40% of acetic acid-acetic anhydride solution of p-fluoroacetanilide and 68% of nitric acid to be 40.0-100.0 mL/min and 4.0-30.0 mL/min, and preheating; carrying out reaction for 50-200 s at 30-70 ℃; and carrying out hydrolysis reaction at 90-100 ℃ for 2-4 h, stirring in ice water at 0-5 ℃ for 0.5h, filtering, washing a filter cake to be weakly acidic or neutral, adding petroleum ether, mixing, and drying to obtain the orange solid 4-fluoro-2-nitroaniline with the yield of 83-94%. The method has the advantages of short time, high efficiency, few by-products and safe, stable and controllable reaction process.
Description
Technical Field
The invention belongs to the preparation of organic compounds, and relates to a method for synthesizing 4-fluoro-2-nitroaniline by a microchannel reactor. The 4-fluoro-2-nitroaniline prepared by the invention is suitable for being used as a pharmaceutical chemical intermediate.
Background
4-fluoro-2-nitroaniline is an important pharmaceutical chemical intermediate, and the market demand is increasing every year. The synthesis method is also divided into different types according to different used raw materials, and the synthesis method of the 4-fluoro-2-nitroaniline is mainly based on nitration at present. However, the existing 4-fluoro-2-nitroaniline synthesis process basically has the problems of complex process operation, long reaction time, low yield and the like, and the nitration reaction in a conventional kettle type reactor has the defects of difficult process control, concentrated reaction heat, easy temperature rise, large amount of side reactions caused by the rapid rise of the temperature, even explosion in serious conditions and huge potential safety hazard.
In The prior art, document 1 (Pagoria P F, Mitchell A R, Schmidt R D.1, 1, 1-Trimethylhydroazinium Iodide: A Novel, high Reactive Reagent for aromatic catalysis via Vicarious nucleic acid catalysis of Hydrogen [ J ] The journal of Organic Chemistry 1996,61(9): 2934-2935.) (Philips-gulia, Alexander-Michel, Robert-Schmidt. 1,1, 1-Trimethylhydrazinium Iodide: a Novel Highly Reactive Reagent [ J ]. J ORG CHEM,1996,61(9): 2934-nitroaniline by Nucleophilic Substitution of Hydrogen in The tert-butyl alcohol and potassium-dimethyl sulfoxide system, with only 4% yield of 4-nitro aniline in The tert-butyl alcohol system, 2% yield was reported. CN109553534A reports a method of synthesizing a target product by using 1, 4-difluorobenzene to firstly nitrify and then ammonolyze, wherein ammonia gas is highly irritant and corrosive, is very easy to burn mucosa of skin, eyes and respiratory organs, is inhaled too much and can cause lung swelling, and 1, 4-difluorobenzene is a relatively expensive reagent, so that the industrial production can significantly increase the production cost. Document 2 (Leyva S, Castanedo V, Leyva E. Synthesis of novel fluorobenzofurans by oxidation of anilides and thermal cyclization of arylazides [ J ]. Journal of fluorination, 2003, 121(2): 171-175.) (Socollo-Lawa, Victorduo-casstao, Irissa-Lawa. Synthesis of novel fluorobenzofuran compounds [ J ]. J FLUORINECHEM, 2003, 121(2): 171-175.) by oxidation of anilines and thermal cyclization of azides, fluoroaniline was used to prepare 4-fluoro-2-nitroaniline by nitration and hydrolysis reaction, but this Synthesis method was complicated in operation, large in solvent, and the yield was only 54% consumption.
Disclosure of Invention
The invention aims to overcome the defects in the prior art and provides a method for synthesizing 4-fluoro-2-nitroaniline by using a microchannel reactor. The invention only depends on the kinetic energy of the fluid to complete the nitration reaction, and provides the method for synthesizing the 4-fluoro-2-nitroaniline by the microchannel reactor, which has the advantages of short reaction time, high production efficiency, less byproducts, safer, more stable and controllable reaction process.
The content of the invention is as follows: a method for synthesizing 4-fluoro-2-nitroaniline by a microchannel reactor is characterized by comprising the following steps:
a. preparation of reactor and feed:
preparing a corning high-flux continuous flow microchannel reactor as a reactor;
the corning high-flux continuous flow microchannel reactor comprises a direct-current preheating module, an enhanced mass transfer mixing module and an outlet;
acetic acid-acetic anhydride solution of p-fluoroacetanilide with the mass percentage concentration of 20-40%, petroleum ether and nitric acid aqueous solution with the mass percentage concentration of 68% are taken as raw materials for standby;
in the acetic acid-acetic anhydride solution of the p-fluoroacetanilide, the molar ratio of the solvent acetic acid to acetic anhydride is acetic acid: acetic anhydride = 1: 1.8 to 2.4;
the molar ratio of the p-fluoroacetanilide to the nitric acid is 1: 1.0 to 1.5;
b. synthesizing 4-fluoro-2-nitroaniline:
adopting a corning high-flux continuous flow microchannel reactor, setting the flow rate of an acetic acid-acetic anhydride solution of p-fluoroacetanilide (metering pump) to be 40.0-100.0 mL/min and the flow rate of a nitric acid aqueous solution (metering pump) to be 4.0-30.0 mL/min, respectively pumping the acetic acid-acetic anhydride solution of p-fluoroacetanilide and the nitric acid aqueous solution into the corning high-flux continuous flow microchannel reactor, and preheating in a first module, namely a direct-current preheating module, at the temperature of 30-70 ℃ and independent of each other; then respectively entering a second module, namely an enhanced mass transfer type mixing module, through an inlet A or an inlet B of the corning high-flux continuous flow microchannel reactor, carrying out mixing reaction for 50-200 s at the reaction temperature of 30-70 ℃, and allowing the reacted mixed liquid to flow out of an outlet of the corning high-flux continuous flow microchannel reactor; then the mixture enters an acid liquid hydrolysis reaction kettle, and hydrolysis reaction is carried out for 2-4 h at the temperature of 90-100 ℃ to obtain a reaction liquid containing a product; the product-containing reaction solution is added into an acid solution hydrolysis reaction kettle containing ice water at the temperature of 0-5 ℃ while stirring, the mixture is filtered after stirring for 0.5h, the obtained filter cake is washed for 2-3 times by the ice water at the temperature of 0-5 ℃ until the filter cake is faintly acid or neutral, then a proper amount of petroleum ether is added for mixing (pulping or crushing once), and drying is carried out, so that the (orange solid) 4-fluoro-2-nitroaniline is prepared, the yield is 83-94%, and the liquid phase purity is 99.5-99.8%.
The invention comprises the following steps: the Corning high-flux continuous flow microchannel reactor in the step a comprises a direct-flow preheating module and an enhanced mass transfer type mixing module, and can be a direct-flow (microchannel) preheating module and a T-shaped microchannel enhanced mass transfer type mixing module respectively, or a direct-flow (microchannel) preheating module and a spherical microchannel enhanced mass transfer type mixing module, or a direct-flow (microchannel) preheating module plus a heart-shaped microchannel enhanced mass transfer type mixing module (any one of three reaction modules), wherein the (reaction) module (and accessories) is made of stainless steel metal or polytetrafluoroethylene coated with a monocrystalline silicon layer, a special glass layer and a corrosion-resistant layer.
The invention comprises the following steps: the structure of the direct-current type preheating module is a direct-current type tubular channel structure, and the diameter of the channel is 0.5-10.0 mm.
The invention comprises the following steps: the structure of the mass transfer enhancement type mixing module is one of a T-shaped channel structure (corresponding to the T-shaped micro-channel mass transfer enhancement type mixing module), a spherical channel structure (corresponding to the spherical micro-channel mass transfer enhancement type mixing module) or a heart-shaped channel structure (corresponding to the heart-shaped micro-channel mass transfer enhancement type mixing module).
The invention comprises the following steps: the flow rate of the acetic acid-acetic anhydride solution of p-fluoroacetanilide in step b is preferably from 40.0mL/min to 90.0.mL/min, and the flow rate of the aqueous nitric acid solution is preferably from 4.0mL/min to 26.9 mL/min.
The invention comprises the following steps: in the step b, the reaction temperature is preferably 30 to 60 ℃.
The invention comprises the following steps: the drying in step b is preferably carried out at a temperature of 50 ℃ for 12h under vacuum.
Compared with the prior art, the invention has the following characteristics and beneficial effects:
(1) the invention adopts the prior corning high-flux continuous flow micro-channel reactor as a reactor, the micro-channel reactor is a continuous flow pipeline type small reaction system manufactured by micro-processing and fine processing technologies, has unique integral design of multilayer structure, and has large surface area to volume ratio compared with the conventional tubular reactor, so the micro-channel reactor has extremely high mixing efficiency and heat exchange capacity, and the mixing effect of the micro-channel reactor on the total heat exchange rate and fluid has incomparable advantages compared with the conventional kettle type reactor, thereby not only greatly shortening the reaction period, but also avoiding the temperature runaway phenomenon caused by local overheating caused by uneven material mixing in the reaction process; in addition, because the size of the channel of the process fluid in the microchannel reactor is very small, the on-line material retention of each reaction module is small, and the materials are instantly and uniformly mixed in an accurate proportion, the reaction process is safer and more efficient; the microchannel reactor can easily realize the amplification of the process through the parallel connection of the devices, does not need a pilot test, has good repeatability and almost no amplification effect, and can greatly improve the flexibility and the safety of production; therefore, compared with the traditional tubular reactor, the device has incomparable advantages in nitration by utilizing the microchannel reactor;
(2) the acetic anhydride can react with water generated in the reaction process to obtain the acetic acid, and water generated in the nitration process can be consumed, so that the reverse reaction of nitration is inhibited, and the occurrence of the nitration reaction is promoted; in addition, acetic anhydride reacts with water to generate acetic acid, so that the concentration of acid in a reaction system can be increased, and a promoting effect is also realized on the subsequent hydrolysis reaction; meanwhile, acetic acid generated in the nitration process is used as a hydrolysis solvent for hydrolysis, so that the feeding is not required again, the production efficiency is improved, the production cost is greatly reduced, the use of reagents is reduced, and the method has the characteristic of environmental friendliness and is easy for industrial production; the continuous microchannel reactor has the characteristics of unique integral design of multilayer structure, large surface area-to-volume ratio, high mixing efficiency and heat exchange capacity, small channel size, small material retention, uniform material instantaneous mixing and the like, not only solves the problems of complex process operation, long reaction time, high byproduct, easy danger of temperature-runaway explosion and the like existing in the production of the traditional kettle type mechanical stirring reactor in the industrial production, but also simplifies the synthesis steps, improves the reaction efficiency, effectively controls the reaction temperature in a safe range, eliminates local overheating and obviously reduces the risk of out-of-control; meanwhile, the reaction module and the fittings of the continuous microchannel reactor are made of special materials, so that the corrosion resistance is high, and the serious problem of equipment corrosion in the nitration process is solved; the microchannel reactor can realize accurate control on temperature and flow under the control of the efficient heat exchanger and the accurate metering pump, has good repeatability, greatly improves the flexibility and safety of production, and can realize safe and efficient production;
(3) in the invention, the organic solvent solution of p-fluoroacetanilide is used as a raw material to carry out nitration in a continuous microchannel reactor, and the 4-fluoro-2-nitroaniline is synthesized by post-treatment; the conventional kettle type mechanical stirring reactor is not adopted for nitration, the nitration reaction is completed only by the kinetic energy of the fluid, the reaction time is short, the production efficiency is high, the byproducts are few, and the reaction process is safer, more stable and controllable; the product has simple preparation process, easy operation and strong practicability.
Drawings
FIG. 1 is a nuclear magnetic spectrum of 4-fluoro-2-nitroaniline synthesized in example 1; the figure illustrates that 4-fluoro-2-nitroaniline is successfully synthesized by adopting a corning high-flux continuous flow microchannel reactor;
FIG. 2 is a schematic diagram of a DC-type microchannel structure of a straight channel preheating module of a Corning high-throughput continuous-flow microchannel reactor used in the embodiments of the present invention;
FIG. 3 is a schematic diagram of a T-shaped microchannel configuration of a second module mixing module of the corning high throughput continuous flow microchannel reactor employed in embodiments of the present invention;
FIG. 4 is a schematic diagram of a spherical microchannel structure of a second module mixing module of the corning high throughput continuous flow microchannel reactor employed in the present invention and embodiments;
FIG. 5 is a schematic diagram of a mixing module of a second module of the corning high throughput continuous flow microchannel reactor used in the embodiments of the present invention.
Detailed Description
The following examples are given to further illustrate the present invention and should not be construed as limiting the scope of the invention, which is intended to be covered by the claims appended hereto.
Example 1:
a method for synthesizing 4-fluoro-2-nitroaniline by a microchannel reactor comprises the following steps:
a. preparation of reactor and feed:
preparing a corning high-flux continuous flow microchannel reactor (a direct-flow microchannel preheating module and a T-shaped microchannel enhanced mass transfer type mixing module) as a reactor, determining the number of the mixing reaction modules according to the flow velocity and the reaction residence time, and using heat transfer oil as a heat exchange medium;
the corning high-flux continuous flow microchannel reactor comprises a direct-current type preheating module (namely a direct-current type microchannel preheating module), an enhanced mass transfer type mixing module (namely a T-shaped microchannel enhanced mass transfer type mixing module) and an outlet;
taking 20 mass percent of acetic acid-acetic anhydride solution of p-fluoroacetanilide, petroleum ether and 68 mass percent of nitric acid aqueous solution as raw materials for later use;
in the acetic acid-acetic anhydride solution of the p-fluoroacetanilide, the molar ratio of the solvent acetic acid to acetic anhydride is acetic acid: acetic anhydride = 1.0: 1.8;
the molar ratio of the p-fluoroacetanilide to the nitric acid is 1.0: 1.0;
b. synthesizing 4-fluoro-2-nitroaniline:
adopting a Corning high-flux continuous flow microchannel reactor, taking the molar ratio of p-fluoroacetanilide to nitric acid as 1.0:1.0 as a reference, respectively setting the flow rate of an acetic acid-acetic anhydride solution metering pump of the p-fluoroacetanilide to be 40.0mL/min and the flow rate of a nitric acid metering pump to be 4.0mL/min, and respectively pumping the acetic acid-acetic anhydride solution of the p-fluoroacetanilide and the nitric acid into a first independent module, namely a direct-flow preheating module, in the Corning high-flux continuous flow microchannel reactor at the temperature of 30 ℃ for preheating; then respectively enters a second module, namely an enhanced mass transfer type mixing module, through an inlet A or an inlet B of the corning high-flux continuous flow microchannel reactor, the mixed reaction is carried out for 50s at the reaction temperature of 30 ℃, and the mixed liquid after the reaction flows out from an outlet of the corning high-flux continuous flow microchannel reactor; then the mixture enters an acid liquid hydrolysis reaction kettle, and hydrolysis reaction is carried out for 4 hours at the temperature of 100 ℃ to obtain reaction liquid containing products; adding the product-containing reaction solution into an acid solution hydrolysis reaction kettle containing ice water at the temperature of 0-5 ℃ under the stirring condition, stirring for 0.5h, filtering, washing the obtained filter cake for 2-3 times by using the ice water at the temperature of 0-5 ℃ until the filter cake is faintly acid or neutral, adding a proper amount of petroleum ether, pulping or crushing for one time, and performing vacuum drying at the temperature of 50 ℃ for 12h to obtain orange solid 4-fluoro-2 nitroaniline, wherein the yield is 83% and the liquid phase purity is 99.6%.
Example 2:
a method for synthesizing 4-fluoro-2-nitroaniline by a microchannel reactor comprises the following steps:
a. preparation of reactor and feed:
preparing a corning high-flux continuous flow microchannel reactor (a direct-flow microchannel preheating module and a spherical microchannel enhanced mass transfer type mixing module) as a reactor, determining the number of the mixed reaction modules according to the flow rate and the reaction residence time, and using heat transfer oil as a heat exchange medium;
the corning high-flux continuous flow microchannel reactor comprises a direct-current type preheating module (namely a direct-current type microchannel preheating module), an enhanced mass transfer type mixing module (namely a spherical microchannel enhanced mass transfer type mixing module) and an outlet;
taking an acetic acid-acetic anhydride solution of p-fluoroacetanilide with the mass percent concentration of 30%, petroleum ether and a nitric acid aqueous solution with the mass percent concentration of 68% as raw materials for later use;
in the acetic acid-acetic anhydride solution of the p-fluoroacetanilide, the molar ratio of the solvent acetic acid to acetic anhydride is acetic acid: acetic anhydride = 1.0: 2.0;
the molar ratio of the p-fluoroacetanilide to the nitric acid is 1.0: 1.2;
b. synthesizing 4-fluoro-2-nitroaniline:
adopting a corning high-flux continuous flow microchannel reactor, taking the molar ratio of p-fluoroacetanilide to nitric acid as 1.0: 1.2 as a reference, respectively setting the flow rate of an acetic acid-acetic anhydride solution metering pump of the p-fluoroacetanilide to be 70.0mL/min and the flow rate of a nitric acid metering pump to be 12.6mL/min, and respectively pumping the acetic acid-acetic anhydride solution of the p-fluoroacetanilide and the nitric acid into a first module, namely a direct-flow preheating module, which is independent of each other and has the temperature of 40 ℃ in the corning high-flux continuous flow microchannel reactor for preheating; then respectively entering a second module, namely an enhanced mass transfer type mixing module, through an inlet A or an inlet B of the corning high-flux continuous flow microchannel reactor, carrying out mixing reaction for 100s at the reaction temperature of 40 ℃, and enabling the reacted mixed liquid to flow out of an outlet of the corning high-flux continuous flow microchannel reactor; then the mixture enters an acid liquid hydrolysis reaction kettle, and hydrolysis reaction is carried out for 4 hours at the temperature of 100 ℃ to obtain reaction liquid containing products; adding the product-containing reaction solution into an acid solution hydrolysis reaction kettle containing ice water at the temperature of 0-5 ℃ under the stirring condition, stirring for 0.5h, filtering, washing the obtained filter cake for 2-3 times by using the ice water at the temperature of 0-5 ℃ until the filter cake is faintly acid or neutral, adding a proper amount of petroleum ether, pulping or crushing for one time, and performing vacuum drying at the temperature of 50 ℃ for 12h to obtain orange solid 4-fluoro-2 nitroaniline, wherein the yield is 92% and the liquid phase purity is 99.7%.
Example 3:
a method for synthesizing 4-fluoro-2-nitroaniline by a microchannel reactor comprises the following steps:
a. preparation of reactor and feed:
preparing a corning high-flux continuous flow microchannel reactor (a direct-flow microchannel preheating module and a heart-shaped microchannel enhanced mass transfer type mixing module) as a reactor, determining the number of the mixing reaction modules according to the flow velocity and the reaction residence time, and using heat transfer oil as a heat exchange medium;
the corning high-flux continuous flow microchannel reactor comprises a direct-current type preheating module (namely a direct-current type microchannel preheating module), an enhanced mass transfer type mixing module (namely a heart-shaped microchannel enhanced mass transfer type mixing module) and an outlet;
taking 35% by mass of acetic acid-acetic anhydride solution of p-fluoroacetanilide, petroleum ether and 68% by mass of nitric acid aqueous solution as raw materials for later use;
in the acetic acid-acetic anhydride solution of the p-fluoroacetanilide, the molar ratio of the solvent acetic acid to acetic anhydride is acetic acid: acetic anhydride = 1.0: 2.2;
the molar ratio of the p-fluoroacetanilide to the nitric acid is 1.0: 1.3;
b. synthesizing 4-fluoro-2-nitroaniline:
adopting a corning high-flux continuous flow microchannel reactor, taking the molar ratio of p-fluoroacetanilide to nitric acid as 1.0: 1.3 as a reference, respectively setting the flow rate of an acetic acid-acetic anhydride solution metering pump of the p-fluoroacetanilide to be 78.0mL/min and the flow rate of a nitric acid metering pump to be 17.7mL/min, and respectively pumping the acetic acid-acetic anhydride solution of the p-fluoroacetanilide and the nitric acid into a first independent module, namely a direct-flow preheating module, of the corning high-flux continuous flow microchannel reactor, wherein the temperature of the first independent module is 50 ℃; then respectively enters a second module, namely an enhanced mass transfer type mixing module, through an inlet A or an inlet B of the corning high-flux continuous flow microchannel reactor, the mixed reaction is carried out for 150s at the reaction temperature of 50 ℃, and the mixed liquid after the reaction flows out from an outlet of the corning high-flux continuous flow microchannel reactor; then the mixture enters an acid liquid hydrolysis reaction kettle, and hydrolysis reaction is carried out for 4 hours at the temperature of 100 ℃ to obtain reaction liquid containing products; adding the product-containing reaction solution into an acid solution hydrolysis reaction kettle containing ice water at the temperature of 0-5 ℃ under the stirring condition, stirring for 0.5h, filtering, washing the obtained filter cake for 2-3 times by using the ice water at the temperature of 0-5 ℃ until the filter cake is weakly acidic or neutral, adding a proper amount of petroleum ether, pulping or crushing for one time, and performing vacuum drying at the temperature of 50 ℃ for 12h to obtain orange solid 4-fluoro-2 nitroaniline, wherein the yield is 93%, and the liquid phase purity is 99.6%.
Example 4:
a method for synthesizing 4-fluoro-2-nitroaniline by a microchannel reactor comprises the following steps:
a. preparation of reactor and feed:
preparing a corning high-flux continuous flow microchannel reactor (a direct-flow microchannel preheating module and a T-shaped microchannel enhanced mass transfer type mixing module) as a reactor, determining the number of the mixing reaction modules according to the flow velocity and the reaction residence time, and using heat transfer oil as a heat exchange medium;
the corning high-flux continuous flow microchannel reactor comprises a direct-current type preheating module (namely a direct-current type microchannel preheating module), an enhanced mass transfer type mixing module (namely a T-shaped microchannel enhanced mass transfer type mixing module) and an outlet;
taking an acetic acid-acetic anhydride solution of p-fluoroacetanilide with the mass percentage concentration of 40%, petroleum ether and a nitric acid aqueous solution with the mass percentage concentration of 68% as raw materials for later use;
in the acetic acid-acetic anhydride solution of the p-fluoroacetanilide, the molar ratio of the solvent acetic acid to acetic anhydride is acetic acid: acetic anhydride = 1.0: 2.4;
the molar ratio of the p-fluoroacetanilide to the nitric acid is 1.0: 1.5;
b. synthesizing 4-fluoro-2-nitroaniline:
adopting a corning high-flux continuous flow microchannel reactor, taking the molar ratio of p-fluoroacetanilide to nitric acid as 1.0: 1.5 as a reference, respectively setting the flow rate of an acetic acid-acetic anhydride solution metering pump of the p-fluoroacetanilide to be 90.0mL/min and the flow rate of a nitric acid metering pump to be 26.9mL/min, and respectively pumping the acetic acid-acetic anhydride solution of the p-fluoroacetanilide and the nitric acid into a first independent module, namely a direct-flow preheating module, of the corning high-flux continuous flow microchannel reactor, wherein the temperature of the first independent module is 60 ℃; then respectively enters a second module, namely an enhanced mass transfer type mixing module, through an inlet A or an inlet B of the corning high-flux continuous flow microchannel reactor, and performs mixing reaction for 200s at the reaction temperature of 60 ℃, and the mixed liquid after the reaction flows out from an outlet of the corning high-flux continuous flow microchannel reactor; then the mixture enters an acid liquid hydrolysis reaction kettle, and hydrolysis reaction is carried out for 4 hours at the temperature of 100 ℃ to obtain reaction liquid containing products; adding the product-containing reaction solution into an acid solution hydrolysis reaction kettle containing ice water at the temperature of 0-5 ℃ under the stirring condition, stirring for 0.5h, filtering, washing the obtained filter cake for 2-3 times by using the ice water at the temperature of 0-5 ℃ until the filter cake is weakly acidic or neutral, adding a proper amount of petroleum ether, pulping or crushing for one time, and performing vacuum drying at the temperature of 50 ℃ for 12h to obtain orange solid 4-fluoro-2 nitroaniline, wherein the yield is 93%, and the liquid phase purity is 99.5%.
Example 5:
a method for synthesizing 4-fluoro-2-nitroaniline by a microchannel reactor comprises the following steps:
a. preparation of reactor and feed:
preparing a corning high-flux continuous flow microchannel reactor as a reactor;
the corning high-flux continuous flow microchannel reactor comprises a direct-current preheating module, an enhanced mass transfer mixing module and an outlet;
taking 20 mass percent of acetic acid-acetic anhydride solution of p-fluoroacetanilide, petroleum ether and 68 mass percent of nitric acid aqueous solution as raw materials for later use;
in the acetic acid-acetic anhydride solution of the p-fluoroacetanilide, the molar ratio of the solvent acetic acid to acetic anhydride is acetic acid: acetic anhydride = 1: 1.8;
the molar ratio of the p-fluoroacetanilide to the nitric acid is 1: 1.0;
b. synthesizing 4-fluoro-2-nitroaniline:
adopting a corning high-flux continuous flow microchannel reactor, setting the flow rate of an acetic acid-acetic anhydride solution of p-fluoroacetanilide (a metering pump) to be 100.0mL/min and the flow rate of a nitric acid aqueous solution (the metering pump) to be 30.0mL/min, respectively pumping the acetic acid-acetic anhydride solution of p-fluoroacetanilide and the nitric acid aqueous solution into the corning high-flux continuous flow microchannel reactor, and preheating in a first module, namely a direct-current preheating module, which is at the temperature of 30 ℃ and is independent of each other; then respectively entering a second module, namely an enhanced mass transfer type mixing module, through an inlet A or an inlet B of the corning high-flux continuous flow microchannel reactor, carrying out mixing reaction for 200s at the reaction temperature of 30 ℃, and enabling the reacted mixed liquid to flow out of an outlet of the corning high-flux continuous flow microchannel reactor; then the mixture enters an acid liquid hydrolysis reaction kettle, and hydrolysis reaction is carried out for 4 hours at the temperature of 90 ℃ to obtain reaction liquid containing products; adding the product-containing reaction solution into an acid solution hydrolysis reaction kettle containing ice water at the temperature of 0-5 ℃ while stirring, stirring for 0.5h, filtering, washing the obtained filter cake with the ice water at the temperature of 0-5 ℃ for 2-3 times until the filter cake is weakly acidic or neutral, adding a proper amount of petroleum ether, mixing (pulping or crushing once), and drying to obtain the (orange solid) 4-fluoro-2 nitroaniline.
Example 6:
a method for synthesizing 4-fluoro-2-nitroaniline by a microchannel reactor comprises the following steps:
a. preparation of reactor and feed:
preparing a corning high-flux continuous flow microchannel reactor as a reactor;
the corning high-flux continuous flow microchannel reactor comprises a direct-current preheating module, an enhanced mass transfer mixing module and an outlet;
taking an acetic acid-acetic anhydride solution of p-fluoroacetanilide with the mass percentage concentration of 40%, petroleum ether and a nitric acid aqueous solution with the mass percentage concentration of 68% as raw materials for later use;
in the acetic acid-acetic anhydride solution of the p-fluoroacetanilide, the molar ratio of the solvent acetic acid to acetic anhydride is acetic acid: acetic anhydride = 1: 2.4;
the molar ratio of the p-fluoroacetanilide to the nitric acid is 1: 1.5;
b. synthesizing 4-fluoro-2-nitroaniline:
adopting a corning high-flux continuous flow microchannel reactor, setting the flow rate of an acetic acid-acetic anhydride solution of p-fluoroacetanilide (a metering pump) to be 40.0mL/min and the flow rate of a nitric acid aqueous solution (the metering pump) to be 4.0mL/min, respectively pumping the acetic acid-acetic anhydride solution of p-fluoroacetanilide and the nitric acid aqueous solution into the corning high-flux continuous flow microchannel reactor, and preheating in a first module, namely a direct-current preheating module, which is at 70 ℃ and is independent of each other; then respectively entering a second module, namely an enhanced mass transfer type mixing module, through an inlet A or an inlet B of the corning high-flux continuous flow microchannel reactor, carrying out mixing reaction for 50s at the reaction temperature of 70 ℃, and enabling the reacted mixed liquid to flow out of an outlet of the corning high-flux continuous flow microchannel reactor; then the mixture enters an acid liquid hydrolysis reaction kettle and undergoes hydrolysis reaction for 2 hours at the temperature of 100 ℃ to obtain a reaction liquid containing a product; adding the product-containing reaction solution into an acid solution hydrolysis reaction kettle containing ice water at the temperature of 0-5 ℃ while stirring, stirring for 0.5h, filtering, washing the obtained filter cake with the ice water at the temperature of 0-5 ℃ for 2-3 times until the filter cake is weakly acidic or neutral, adding a proper amount of petroleum ether, mixing (pulping or crushing once), and drying to obtain the (orange solid) 4-fluoro-2 nitroaniline.
Example 7:
a method for synthesizing 4-fluoro-2-nitroaniline by a microchannel reactor comprises the following steps:
a. preparation of reactor and feed:
preparing a corning high-flux continuous flow microchannel reactor as a reactor;
the corning high-flux continuous flow microchannel reactor comprises a direct-current preheating module, an enhanced mass transfer mixing module and an outlet;
taking an acetic acid-acetic anhydride solution of p-fluoroacetanilide with the mass percent concentration of 30%, petroleum ether and a nitric acid aqueous solution with the mass percent concentration of 68% as raw materials for later use;
in the acetic acid-acetic anhydride solution of the p-fluoroacetanilide, the molar ratio of the solvent acetic acid to acetic anhydride is acetic acid: acetic anhydride = 1: 2.1;
the molar ratio of the p-fluoroacetanilide to the nitric acid is 1: 1.25;
b. synthesizing 4-fluoro-2-nitroaniline:
adopting a corning high-flux continuous flow microchannel reactor, setting the flow rate of an acetic acid-acetic anhydride solution of p-fluoroacetanilide (a metering pump) to be 60.0mL/min and the flow rate of a nitric acid aqueous solution (the metering pump) to be 16.0mL/min, respectively pumping the acetic acid-acetic anhydride solution of p-fluoroacetanilide and the nitric acid aqueous solution into the corning high-flux continuous flow microchannel reactor, and preheating in a first module, namely a direct-current preheating module, at the temperature of 55 ℃ and independent of each other; then respectively enters a second module, namely an enhanced mass transfer type mixing module, through an inlet A or an inlet B of the corning high-flux continuous flow microchannel reactor, the mixed reaction is carried out for 130s at the reaction temperature of 55 ℃, and the mixed liquid after the reaction flows out from an outlet of the corning high-flux continuous flow microchannel reactor; then the mixture enters an acid liquid hydrolysis reaction kettle, and hydrolysis reaction is carried out for 3 hours at the temperature of 150 ℃ to obtain reaction liquid containing products; adding the product-containing reaction solution into an acid solution hydrolysis reaction kettle containing ice water at the temperature of 0-5 ℃ while stirring, stirring for 0.5h, filtering, washing the obtained filter cake with the ice water at the temperature of 0-5 ℃ for 2-3 times until the filter cake is weakly acidic or neutral, adding a proper amount of petroleum ether, mixing (pulping or crushing once), and drying to obtain the (orange solid) 4-fluoro-2 nitroaniline.
Example 8:
a method for synthesizing 4-fluoro-2-nitroaniline by a microchannel reactor comprises the following steps:
a. preparation of reactor and feed:
preparing a corning high-flux continuous flow microchannel reactor as a reactor;
the corning high-flux continuous flow microchannel reactor comprises a direct-current preheating module, an enhanced mass transfer mixing module and an outlet;
acetic acid-acetic anhydride solution of p-fluoroacetanilide with the mass percentage concentration of 20-40%, petroleum ether and nitric acid aqueous solution with the mass percentage concentration of 68% are taken as raw materials for standby;
in the acetic acid-acetic anhydride solution of the p-fluoroacetanilide, the molar ratio of the solvent acetic acid to acetic anhydride is acetic acid: acetic anhydride = 1: 1.8 to 2.4;
the molar ratio of the p-fluoroacetanilide to the nitric acid is 1: 1.0 to 1.5;
b. synthesizing 4-fluoro-2-nitroaniline:
adopting a corning high-flux continuous flow microchannel reactor, setting the flow rate of an acetic acid-acetic anhydride solution of p-fluoroacetanilide (metering pump) to be 40.0-100.0 mL/min and the flow rate of a nitric acid aqueous solution (metering pump) to be 4.0-30.0 mL/min, respectively pumping the acetic acid-acetic anhydride solution of p-fluoroacetanilide and the nitric acid aqueous solution into the corning high-flux continuous flow microchannel reactor, and preheating in a first module, namely a direct-current preheating module, at the temperature of 30-70 ℃ and independent of each other; then respectively entering a second module, namely an enhanced mass transfer type mixing module, through an inlet A or an inlet B of the corning high-flux continuous flow microchannel reactor, carrying out mixing reaction for 50-200 s at the reaction temperature of 30-70 ℃, and allowing the reacted mixed liquid to flow out of an outlet of the corning high-flux continuous flow microchannel reactor; then the mixture enters an acid liquid hydrolysis reaction kettle, and hydrolysis reaction is carried out for 2-4 h at the temperature of 90-100 ℃ to obtain a reaction liquid containing a product; the product-containing reaction solution is added into an acid solution hydrolysis reaction kettle containing ice water at the temperature of 0-5 ℃ while stirring, the mixture is filtered after stirring for 0.5h, the obtained filter cake is washed for 2-3 times by the ice water at the temperature of 0-5 ℃ until the filter cake is faintly acid or neutral, then a proper amount of petroleum ether is added for mixing (pulping or crushing once), and drying is carried out, so that the (orange solid) 4-fluoro-2-nitroaniline is prepared, the yield is 83-94%, and the liquid phase purity is 99.5-99.8%.
Example 9:
a method for synthesizing 4-fluoro-2-nitroaniline by a microchannel reactor comprises the following steps:
a. preparation of reactor and feed:
preparing a corning high-flux continuous flow microchannel reactor as a reactor;
the corning high-flux continuous flow microchannel reactor comprises a direct-current preheating module, an enhanced mass transfer mixing module and an outlet;
taking 35% by mass of acetic acid-acetic anhydride solution of p-fluoroacetanilide, petroleum ether and 68% by mass of nitric acid aqueous solution as raw materials for later use;
in the acetic acid-acetic anhydride solution of the p-fluoroacetanilide, the molar ratio of the solvent acetic acid to acetic anhydride is acetic acid: acetic anhydride = 1: 2.3;
the molar ratio of the p-fluoroacetanilide to the nitric acid is 1: 1.4;
b. synthesizing 4-fluoro-2-nitroaniline:
adopting a corning high-flux continuous flow microchannel reactor, setting the flow rate of an acetic acid-acetic anhydride solution of p-fluoroacetanilide (a metering pump) to be 90.0mL/min and the flow rate of a nitric acid aqueous solution (the metering pump) to be 28.0mL/min, respectively pumping the acetic acid-acetic anhydride solution of p-fluoroacetanilide and the nitric acid aqueous solution into the corning high-flux continuous flow microchannel reactor, and preheating in a first module, namely a direct-current preheating module, which is at the temperature of 60 ℃ and is independent of each other; then respectively entering a second module, namely an enhanced mass transfer type mixing module, through an inlet A or an inlet B of the corning high-flux continuous flow microchannel reactor, carrying out mixing reaction for 100s at the reaction temperature of 60 ℃, and enabling the reacted mixed liquid to flow out of an outlet of the corning high-flux continuous flow microchannel reactor; then the mixture enters an acid liquid hydrolysis reaction kettle, and hydrolysis reaction is carried out for 3 hours at the temperature of 95 ℃ to obtain reaction liquid containing products; adding the product-containing reaction solution into an acid solution hydrolysis reaction kettle containing ice water at the temperature of 0-5 ℃ while stirring, stirring for 0.5h, filtering, washing the obtained filter cake with the ice water at the temperature of 0-5 ℃ for 2-3 times until the filter cake is weakly acidic or neutral, adding a proper amount of petroleum ether, mixing (pulping or crushing once), and drying to obtain the (orange solid) 4-fluoro-2 nitroaniline.
In examples 5 to 9 above: the Corning high-flux continuous flow microchannel reactor in the step a comprises a direct-flow preheating module and an enhanced mass transfer type mixing module, and can be a direct-flow (microchannel) preheating module and a T-shaped microchannel enhanced mass transfer type mixing module respectively, or a direct-flow (microchannel) preheating module and a spherical microchannel enhanced mass transfer type mixing module, or a direct-flow (microchannel) preheating module plus a heart-shaped microchannel enhanced mass transfer type mixing module (any one of three reaction modules), wherein the (reaction) module (and accessories) is made of stainless steel metal or polytetrafluoroethylene coated with a monocrystalline silicon layer, a special glass layer and a corrosion-resistant layer.
In examples 5 to 9 above: the structure of the direct-current type preheating module is a direct-current type tubular channel structure, and the diameter of the channel is one of 0.5 mm-10.0 mm.
In examples 5 to 9 above: the structure of the mass transfer enhancement type mixing module is one of a T-shaped channel structure (corresponding to the T-shaped micro-channel mass transfer enhancement type mixing module), a spherical channel structure (corresponding to the spherical micro-channel mass transfer enhancement type mixing module) or a heart-shaped channel structure (corresponding to the heart-shaped micro-channel mass transfer enhancement type mixing module).
In examples 5 to 9 above: in the step b, the reaction temperature is preferably 30 to 60 ℃.
In examples 5 to 9 above: the drying in step b is preferably carried out at a temperature of 50 ℃ for 12h under vacuum.
In the above embodiment: the percentages used, not specifically indicated, are percentages by weight or known to those skilled in the art; the proportions used, not specifically noted, are mass (weight) proportions; the parts by weight may each be grams or kilograms.
In the above embodiment: the process parameters (temperature, time, concentration, flow rate, etc.) and the amounts of the components in each step are within ranges, and any point can be applied.
The present invention and the technical contents not specifically described in the above examples are the same as those of the prior art, and the raw materials are all commercially available products.
The present invention is not limited to the above-described embodiments, and the present invention can be implemented with the above-described advantageous effects.
Claims (7)
1. A method for synthesizing 4-fluoro-2-nitroaniline by a microchannel reactor is characterized by comprising the following steps:
a. preparation of reactor and feed:
preparing a corning high-flux continuous flow microchannel reactor as a reactor;
the corning high-flux continuous flow microchannel reactor comprises a direct-current preheating module, an enhanced mass transfer mixing module and an outlet;
acetic acid-acetic anhydride solution of p-fluoroacetanilide with the mass percentage concentration of 20-40%, petroleum ether and nitric acid aqueous solution with the mass percentage concentration of 68% are taken as raw materials for standby;
in the acetic acid-acetic anhydride solution of the p-fluoroacetanilide, the molar ratio of the solvent acetic acid to acetic anhydride is acetic acid: acetic anhydride = 1: 1.8 to 2.4;
the molar ratio of the p-fluoroacetanilide to the nitric acid is 1: 1.0 to 1.5;
b. synthesizing 4-fluoro-2-nitroaniline:
adopting a Corning high-flux continuous flow microchannel reactor, setting the flow rate of an acetic acid-acetic anhydride solution of p-fluoroacetanilide to be 40.0-100.0 mL/min and the flow rate of a nitric acid aqueous solution to be 4.0-30.0 mL/min, respectively pumping the acetic acid-acetic anhydride solution of p-fluoroacetanilide and the nitric acid aqueous solution into the Corning high-flux continuous flow microchannel reactor, and preheating in a first module, namely a direct-current preheating module, which is independent of each other and has the temperature of 30-70 ℃; then respectively entering a second module, namely an enhanced mass transfer type mixing module, through an inlet A or an inlet B of the corning high-flux continuous flow microchannel reactor, carrying out mixing reaction for 50-200 s at the reaction temperature of 30-70 ℃, and allowing the reacted mixed liquid to flow out of an outlet of the corning high-flux continuous flow microchannel reactor; then the mixture enters an acid liquid hydrolysis reaction kettle, and hydrolysis reaction is carried out for 2-4 h at the temperature of 90-100 ℃ to obtain a reaction liquid containing a product; adding the product-containing reaction solution into an acid solution hydrolysis reaction kettle containing ice water at the temperature of 0-5 ℃ while stirring, stirring for 0.5h, filtering, washing the obtained filter cake for 2-3 times by using the ice water at the temperature of 0-5 ℃ until the filter cake is weakly acidic or neutral, adding petroleum ether, mixing, and drying to obtain the 4-fluoro-2-nitroaniline.
2. The process for the synthesis of 4-fluoro-2-nitroaniline according to claim 1 wherein: the Corning high-flux continuous flow microchannel reactor in the step a comprises a direct-flow preheating module and an enhanced mass transfer type mixing module, and is a direct-flow preheating module + T-shaped microchannel enhanced mass transfer type mixing module, or a direct-flow preheating module + spherical microchannel enhanced mass transfer type mixing module, or a direct-flow preheating module + heart-shaped microchannel enhanced mass transfer type mixing module, and the modules are made of stainless steel metal or polytetrafluoroethylene coated with a monocrystalline silicon layer, a special glass layer and a corrosion-resistant layer.
3. A process for the synthesis of 4-fluoro-2-nitroaniline according to the microchannel reactor of claim 1 or 2, characterized in that: the structure of the direct-current type preheating module is a direct-current type tubular channel structure, and the diameter of the channel is 0.5-10.0 mm.
4. A process for the synthesis of 4-fluoro-2-nitroaniline according to the microchannel reactor of claim 1 or 2, characterized in that: the structure of the mass transfer enhancement type mixing module is one of a T-shaped channel structure, a spherical channel structure and a heart-shaped channel structure.
5. A process for the synthesis of 4-fluoro-2-nitroaniline according to the microchannel reactor of claim 1 or 2, characterized in that: the flow rate of the acetic acid-acetic anhydride solution of the p-fluoroacetanilide in the step b is 40.0mL/min to 90.0mL/min, and the flow rate of the nitric acid aqueous solution is 4.0mL/min to 26.9 mL/min.
6. A process for the synthesis of 4-fluoro-2-nitroaniline according to the microchannel reactor of claim 1 or 2, characterized in that: in the step b, the reaction temperature is 30-60 ℃.
7. A process for the synthesis of 4-fluoro-2-nitroaniline according to the microchannel reactor of claim 1 or 2, characterized in that: the drying in step b is carried out at a temperature of 50 ℃ for 12h under vacuum.
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