CN114773201A - Method for rapidly preparing 1-methoxy-4-nitronaphthalene based on micro-channel continuous flow technology - Google Patents
Method for rapidly preparing 1-methoxy-4-nitronaphthalene based on micro-channel continuous flow technology Download PDFInfo
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- CN114773201A CN114773201A CN202210520752.5A CN202210520752A CN114773201A CN 114773201 A CN114773201 A CN 114773201A CN 202210520752 A CN202210520752 A CN 202210520752A CN 114773201 A CN114773201 A CN 114773201A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/08—Preparation of nitro compounds by substitution of hydrogen atoms by nitro groups
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Abstract
The invention discloses a method for rapidly preparing 1-methoxy-4-nitronaphthalene based on a microchannel continuous flow technology, which comprises the following steps: 1. pumping the nitrating agent and a corresponding solvent into a micro-channel mixer according to a certain proportion, and mixing the nitrating agent and the corresponding solvent into a nitrating agent solution at a certain temperature; 2. pumping the 1-methoxy naphthalene solution and the nitrating agent solution which is mixed on line into a microchannel reactor according to a certain molar ratio, reacting for a certain time at a certain temperature, and nitrating to generate the product 1-methoxy-4-nitronaphthalene. The invention realizes the safe continuous operation of the nitration process by coupling the microchannel continuous flow technology with intrinsic safety, greatly reduces the danger level of nitration reaction, obviously improves the production efficiency, and ensures that the reaction obtains high-purity products with the yield higher than that of a kettle type under the continuous conditions of safety, controllability, environmental protection and high efficiency.
Description
The technical field is as follows:
the invention belongs to the field of organic synthesis of medical intermediates, relates to a synthetic method of 1-methoxy-4-nitronaphthalene, and particularly relates to a method for rapidly preparing 1-methoxy-4-nitronaphthalene by using a microchannel continuous flow technology.
The background art comprises the following steps:
1-methoxy-4-nitronaphthalene, CAS number 4900-63-4, is an important organic intermediate as a naphthalene derivative, has wide application in the fields of molecular medicine, fine chemicals, functional materials and the like, and has high added value. The traditional preparation of 1-methoxy-4-nitronaphthalene takes 1-methoxy naphthalene as a raw material and a mixture of nitric acid and organic acid anhydride as a nitration reagent, and the nitration reaction is carried out in a kettle type reactor. However, the heat of reaction released per introduction of a nitro group is as high as 150KJ/mol, and most nitration reactions are carried out at a high risk level, and thus the nitration reaction is generally carried out under low temperature conditions. In addition, the kettle type reaction generally has an obvious amplification effect, the generated reaction heat is gradually difficult to remove rapidly along with the gradual amplification from small tests, pilot tests to industrial production, more non-ideal flow patterns such as circulation, dead angles and the like can also appear in the kettle, the product quality is influenced, and the danger is further gathered. Therefore, in the industrial production process, if accidents such as failure of a temperature control system, power failure, cooling water stop, sudden stop of a stirring paddle and the like occur, the temperature in the kettle is easy to fly, so that the accidents are caused.
Tetsuya Takeya et al used the conventional kettle-type process in [ HETEROCYCLES,2010, Vol.80, No.2, p.1479-1488], nitric acid was dissolved in acetic anhydride at 0 deg.C, the solution was dropped into acetic anhydride solution of 1-methoxynaphthalene, reacted at 0 deg.C for 4h, then quenched by adding ice water, stirred for 5h, filtered off the solid, and purified by column chromatography to obtain yellow needle-like product with a yield of 50%. Masahito Murai et al dissolved 47.4mg of 1-methoxynaphthalene in [ The Journal of Organic Chemistry,2019, vol.84, #9, p.5667-5676] using 1, 2-dichloroethane as solvent and Fe (NO3) 3.9H 2O as nitrating agent and reacted at room temperature for 5H to give a yellow solid in 82% yield. The method is only suitable for laboratory small-scale research and development, and once the process is amplified, the product quality is influenced due to the amplification effect, and dangerous accidents such as material spraying and the like are caused by delayed heat removal.
The invention patent CN108530242A introduces a green novel free radical nitration: 1-methoxy naphthalene is used as a raw material, nitrile is used as a reaction solvent, a nitration reagent, namely tert-butyl nitrite acetic acid (TBN), is subjected to free radical nitration reaction for 24 hours at room temperature, and column chromatography is carried out to obtain the product with the yield of 56%. Although tert-butyl nitrite vinegar is recognized as a milder nitrating agent, it has some inevitable disadvantages, such as: high toxicity, decomposition and heat release when heated or impacted. In addition, TBN also produces by-products such as t-butanol after radical cracking, which has a certain effect on the purification and yield of the product and is not highly atom economical.
Chawla, H.Mohindra et al [ Synthesis,1985, #1, p.70-72] describe numerous organic reactions on solid inorganic supports, which group applies cerium ammonium nitrate to the oxidative derivatization of aromatic ethers, since reagents adsorbed on silica gel catalyze certain reactions: an acetonitrile solution of 1-methoxynaphthalene and an acetonitrile solution of Ce (NH4)2(NO3)6 were mixed with a corresponding amount of silica gel to form a slurry, and the slurry was dried and then mixed uniformly, and the mixture was purified by column chromatography using a PE/benzene (9/1) elution machine to obtain a product with a yield of 65%. The method effectively avoids the risk factors of nitration reaction, but is only suitable for research and development in a pilot plant stage due to the requirement of a large amount of silica gel and complicated operation, and the operability of scale-up production is not strong.
Microchannel continuous flow technology has developed relatively rapidly in recent years abroad due to its several orders of magnitude higher specific surface area and mass heat transfer coefficient than conventional reactors; the reactor has smaller liquid holdup under the continuous operation of changing the space (yield) by the time (24h without interruption); and very little amplification effect, so that the technology has wide application in dangerous reaction fields such as organic metal reaction, nitration reaction, diazotization and the like within a short time. Aiming at the defects of technology, safety and the like in the existing synthesis of the 1-methoxy-4-nitronaphthalene, the invention couples the traditional synthesis path with the microchannel continuous flow technology, so that the synthesis process is continuous, the danger coefficient of nitration reaction is reduced, the reaction process is safer and more efficient, the amplification effect can be inhibited to the maximum extent by the superposition of the number of microreactors and proper size amplification, and the industrial production is realized.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a method for quickly preparing 1-methoxy-4-nitronaphthalene by using a microchannel continuous flow technology, wherein 1-methoxy naphthalene and a nitrating agent are used as raw materials to carry out nitration reaction in a microreactor to generate 1-methoxy-4-nitronaphthalene, so that a target compound can be synthesized safely, efficiently and stably.
In order to realize the purpose, the invention adopts the following technical scheme:
a method for rapidly preparing 1-methoxy-4-nitronaphthalene based on a microchannel continuous flow technology comprises the following specific steps:
(1) on-line mixing of nitrating agent solution:
pumping the nitrating agent and a corresponding solvent into a micro-channel mixer according to a certain proportion, and mixing the nitrating agent and the corresponding solvent on line at a certain temperature to form a nitrating agent solution;
(2) nitration reaction:
pumping the 1-methoxynaphthalene solution into a microchannel reactor according to a certain proportion, mixing the solution with the nitrating agent solution in the step (1), reacting for a certain time at a certain temperature, and nitrating to generate a product 1-methoxy-4-nitronaphthalene.
The reaction route is as follows:
further, in the step (1), the nitrating agent is at least one of nitric acid, nitrate, nitrogen oxide and acetyl nitrate; preferably, the nitrate is potassium nitrate or sodium nitrate; preferably, the nitrogen oxide is dinitrogen trioxide or dinitrogen tetroxide.
Further, in the step (1), the solvent is at least one of concentrated sulfuric acid, organic acid and acid anhydride; preferably, the organic acid anhydride is acetic anhydride.
Further, in the step (1), the molar ratio of the raw material (1-methoxynaphthalene) to the nitrating agent is 1: 1-1.5; the mass/volume (i.e. the number of volumes of the solvent) of the raw material and the solvent is 1: 1-5.
Preferably, in the step (1), the molar ratio of the raw material to the nitrating agent is 1: 1.1-1.3; the mass/volume ratio of the raw material to the solvent is 1: 1.2-3.
Further, in the step (1), the hydraulic diameter of the single channel and/or the multiple channels in the microchannel mixer is 100-6000 microns; the mixing temperature in the microchannel mixer is-20 ℃ to 10 ℃.
Preferably, in the step (1), the hydraulic diameter of the single channel and/or the multiple channels in the microchannel mixer is 100-2000 microns; the mixing temperature in the microchannel mixer is-5 ℃ to 5 ℃.
Further, in the step (2), the solvent used in the 1-methoxynaphthalene solution is at least one of acetonitrile, acetone, halogenated alkane, concentrated sulfuric acid, organic acid and organic acid anhydride; preferably, the halogenated alkane is at least one of dichloromethane, 1, 2-dichloroethane, chloroform and carbon tetrachloride; preferably, the organic acid is acetic acid; preferably, the organic acid anhydride is acetic anhydride.
Further, in the step (2), the molar ratio of the 1-methoxynaphthalene to the nitrating agent is 1: 1-1.5.
Further, in the step (2), the hydraulic diameter of the single channel and/or the multiple channels in the microchannel reactor is 100-8000 micrometers; the temperature of the nitration reaction is-20 ℃ to 40 ℃, and the reaction residence time is 0.5min to 30 min.
Preferably, in the step (2), the hydraulic diameter of the single channel and/or multiple channels in the microchannel reactor is 100 to 2000 micrometers; the temperature of the nitration reaction is-5 ℃ to 25 ℃, and the reaction residence time is 0.5min to 10 min.
The beneficial effects of the invention are: the invention has the innovation points that the traditional kettle type nitration reaction is changed into a continuous process by coupling a microchannel continuous flow technology with intrinsic safety, so that the danger level of the nitration reaction is greatly reduced, the production efficiency is obviously improved, the amplification effect is inhibited to the greatest extent, the product quality is ensured, and the industrial production is realized. The microchannel reactor has the scale characteristics that the dimension is smaller than that of a conventional kettle reactor by several orders of magnitude, so that the microchannel reactor has a specific surface area and a mass heat transfer coefficient which are far higher than those of the conventional kettle reactor, and can rapidly guide nitration heat out of a reaction system in the industrial scale production process; in addition, under the continuous operation of replacing the space (output) with the time (24h uninterrupted), the liquid holdup of the reactor is far smaller than that of a conventional reactor, and the intrinsic safety of the micro-channel continuous flow reactor is determined by the advantages. Therefore, the invention can lead the reaction to obtain the product with yield superior to that of a kettle type and equivalent purity under the continuous conditions of safety, environmental protection, high efficiency and stability.
Drawings
FIG. 1 is a flow chart of a synthesis process of 1-methoxy-4-nitronaphthalene of the invention:
in the figure: 1-a nitrating agent storage tank; 2-a solvent storage tank for the nitrating agent; 3-a first metering pump; 4-a second metering pump; 5-a microchannel mixer; a 6-1-methoxynaphthalene solution storage tank; 7-a third metering pump; 8-a microchannel reactor; 9-product receiving quench tank; 10-first constant temperature bath; 11-second constant temperature bath.
Detailed Description
The invention is described in detail below with reference to the drawings and the detailed description.
Example 1:
as shown in FIG. 1, 65% nitric acid was charged into a storage tank 1, acetic anhydride was charged into a storage tank 2, an acetic anhydride solution of 1-methoxynaphthalene prepared in advance at a concentration of 1.6M was charged into a storage tank 6, and 65% nitric acid and acetic anhydride were pumped into a microchannel mixer 5 by a first metering pump 3 and a second metering pump 4, respectively, and mixed at a nitric acid concentration of 4.3M and a mixing temperature of 0 ℃ controlled by a first constant temperature bath. Pumping the acetic anhydride solution of the 1-methoxynaphthalene into a microchannel reactor 8 by a third metering pump 7, mixing with the acetic anhydride nitrate solution from the microchannel mixer 5, and reacting at the reaction temperature of 0 ℃ controlled by a second constant temperature bath, wherein the molar equivalent ratio of the 1-methoxynaphthalene to the nitric acid is 1:1.3, and the reaction retention time is 2.5 min. The reaction solution was collected in a product receiving and quenching tank 9 previously filled with ice water. 1ml of dichloromethane is added into 1ml of reaction liquid to dissolve the precipitate, and then an organic phase is taken for chromatographic analysis, wherein the purity of the product in the reaction liquid is 76.3 percent. The collected reaction solution is filtered to obtain precipitate, and the precipitate is recrystallized by absolute ethyl alcohol to obtain the product with the purity of 95.6 percent and the yield of 70 percent.
Example 2:
the specific reaction process is similar to that of example 1, and post-treatment processes such as recrystallization and the like are not performed. The molar equivalent ratio of the 1-methoxynaphthalene to the nitric acid is changed to 1:1.2, and the purity of the product in the obtained reaction liquid is 75.2%.
Example 3:
the specific reaction process is similar to that of example 1, and post-treatment processes such as recrystallization and the like are not performed. The concentration of the mixed nitric acid is changed to 2.3M, the temperature of the second constant temperature bath for nitration reaction is changed to 20 ℃, and the purity of the product in the obtained reaction liquid is 74.3%.
Example 4:
the specific reaction process is similar to that of example 1, and a post-treatment process such as recrystallization is not carried out. The concentration of the mixed nitric acid is changed to 2.3M, the molar equivalent ratio of the 1-methoxynaphthalene to the nitric acid is changed to 1:1.1, the temperature of a second constant temperature bath for nitration is changed to 20 ℃, and the purity of the product in the obtained reaction liquid is 66.8%.
Finally, it should be noted that the above-mentioned contents are only used for illustrating the technical solutions of the present invention, and not for limiting the protection scope of the present invention, and that the simple modifications or equivalent substitutions of the technical solutions of the present invention by those of ordinary skill in the art can be made without departing from the spirit and scope of the technical solutions of the present invention.
Claims (8)
1. A method for rapidly preparing 1-methoxy-4-nitronaphthalene based on a microchannel continuous flow technology is characterized by comprising the following specific steps:
(1) on-line mixing of nitrating agent solution:
pumping the nitrating agent and the solvent into a micro-channel mixer, and mixing the nitrating agent and the solvent into a nitrating agent solution on line; the nitrating agent is at least one of nitric acid, nitrate, nitric oxide and acetyl nitrate; the solvent is at least one of concentrated sulfuric acid, organic acid and organic acid anhydride; the molar ratio of the raw material 1-methoxynaphthalene to the nitrating agent is 1: 1-1.5; the mass/volume of the raw material 1-methoxynaphthalene and the solvent is 1: 1-5;
(2) nitration reaction:
pumping the 1-methoxynaphthalene solution into a microchannel reactor according to a certain proportion, mixing the solution with the nitrating agent solution in the step (1), and nitrating to generate a product 1-methoxy-4-nitronaphthalene; the solvent used in the 1-methoxynaphthalene solution is at least one of acetonitrile, acetone, halogenated alkane, concentrated sulfuric acid, organic acid and organic acid anhydride; the molar ratio of the 1-methoxynaphthalene to the nitrating agent is 1: 1-1.5.
2. The method for rapidly preparing 1-methoxy-4-nitronaphthalene based on the microchannel continuous flow technology according to claim 1, which is characterized in that: in the step (1), the hydraulic diameter of a single channel and/or multiple channels in the micro-channel mixer is 100-6000 microns; the mixing temperature in the microchannel mixer is-20 ℃ to 10 ℃.
3. The method for rapidly preparing 1-methoxy-4-nitronaphthalene based on the microchannel continuous flow technology as claimed in claim 1 or 2, wherein: in the step (2), the hydraulic diameter of a single channel and/or multiple channels in the microchannel reactor is 100-8000 micrometers; the temperature of the nitration reaction is-20 ℃ to 40 ℃, and the reaction residence time is 0.5min to 30 min.
4. The method for rapidly preparing 1-methoxy-4-nitronaphthalene based on the microchannel continuous flow technology as claimed in claim 1 or 2, wherein: in the step (1), the nitrate is potassium nitrate and/or sodium nitrate.
5. The method for rapidly preparing 1-methoxy-4-nitronaphthalene based on the microchannel continuous flow technology as claimed in claim 1 or 2, wherein: in the step (1), the nitrogen oxide is dinitrogen trioxide and/or dinitrogen tetroxide.
6. The method for rapidly preparing 1-methoxy-4-nitronaphthalene based on the microchannel continuous flow technology as claimed in claim 1 or 2, wherein: the organic acid anhydride is acetic anhydride.
7. The method for rapidly preparing 1-methoxy-4-nitronaphthalene based on the microchannel continuous flow technology as claimed in claim 1 or 2, wherein: in the step (2), the halogenated alkane is at least one of dichloromethane, 1, 2-dichloroethane, chloroform and carbon tetrachloride.
8. The method for rapidly preparing 1-methoxy-4-nitronaphthalene based on the microchannel continuous flow technology as claimed in claim 1 or 2, wherein: in the step (2), the organic acid is acetic acid.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104478729A (en) * | 2014-11-24 | 2015-04-01 | 常州大学 | Method for synthesizing 1,5-dinitronaphthalene and 1,8-dinitronaphthalene by continuous flow microchannel reaction |
| CN110590558A (en) * | 2019-10-09 | 2019-12-20 | 蚌埠学院 | Method for catalyzing selective nitration of 1-methoxynaphthalene by using zeolite molecular sieve |
| CN113666907A (en) * | 2021-08-25 | 2021-11-19 | 都创(上海)医药开发有限公司 | Method for rapidly preparing 4-nitrothiophene-2-formic acid based on microchannel reaction technology |
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- 2022-05-12 CN CN202210520752.5A patent/CN114773201A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104478729A (en) * | 2014-11-24 | 2015-04-01 | 常州大学 | Method for synthesizing 1,5-dinitronaphthalene and 1,8-dinitronaphthalene by continuous flow microchannel reaction |
| CN110590558A (en) * | 2019-10-09 | 2019-12-20 | 蚌埠学院 | Method for catalyzing selective nitration of 1-methoxynaphthalene by using zeolite molecular sieve |
| CN113666907A (en) * | 2021-08-25 | 2021-11-19 | 都创(上海)医药开发有限公司 | Method for rapidly preparing 4-nitrothiophene-2-formic acid based on microchannel reaction technology |
Non-Patent Citations (2)
| Title |
|---|
| TETSUYA TAKEYA, ET AL.: "Oxidative dimerization of 4-methoxynaphthylamines in the presence of semiconductors", HETEROCYCLES, vol. 80, no. 2, pages 1479 - 1488 * |
| 魏微 等: "微反应器内的硝化反应研究进展", 染料与染色, vol. 56, no. 6, pages 55 - 60 * |
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