CN112225664B - Preparation method and application of nitrobenzaldehyde and 2-chloro-4-fluoro-5-nitrobenzaldehyde - Google Patents
Preparation method and application of nitrobenzaldehyde and 2-chloro-4-fluoro-5-nitrobenzaldehyde Download PDFInfo
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Abstract
The invention relates to the technical field of preparation methods of organic compounds, and particularly relates to a preparation method and application of nitrobenzaldehyde and 2-chloro-4-fluoro-5-nitrobenzaldehyde. A method for preparing nitrobenzaldehyde comprises the following steps: (1) nitration reaction: adding benzyl dichloride with substituent groups into the mixed solution of sulfuric acid and nitric acid, controlling the reaction temperature to be not higher than 60 ℃, and reacting until the benzyl dichloride with substituent groups completely reacts; (2) hydrolysis reaction: heating the reaction system to 60-120 ℃, and stopping the reaction until the nitration product of the benzyl dichloride with the substituent completely reacts; the structure of the benzyl dichloride with the substituent group is shown as a formula I; the position of the substituent R is at least one of ortho-position, meta-position and para-position; the number of the substituent R is 1-5, and the substituent R is selected from at least one of hydrogen, alkyl and halogen;
Description
Technical Field
The invention relates to the technical field of preparation methods of organic compounds, and particularly relates to a preparation method and application of nitrobenzaldehyde and 2-chloro-4-fluoro-5-nitrobenzaldehyde.
Background
Nitrobenzaldehyde is used as an important fine organic chemical intermediate, has wide industrial application and large demand, and is widely used for medical fuels and organic synthesis. At present, the research on the synthetic route of o-nitrobenzaldehyde and p-nitrobenzaldehyde is wide at home and abroad, and the chemical synthetic method mainly comprises the following steps: oxidative nitration, displacement, reduction, and the like. However, these methods all have common disadvantages: high cost and serious environmental pollution. At present, the method for preparing nitrobenzaldehyde by oxidizing nitrotoluene by an electrochemical method has low efficiency and still stays in a laboratory stage, and especially the synthesis of nitrobenzaldehyde compounds with substituents cannot meet the industrial application.
2-chloro-4-fluoro-5-nitrobenzaldehyde, known as 2-chloro-4-fluoro-5-nitrobenzaldehyde, CAS number 99329-85-8, formula C 7 H 3 Cl F NO 3 The compound is an important organic intermediate for the synthesis of medicines and pesticides, and the chemical structure of the compound is shown as a formula III. At present, in the reports of the synthetic methods of the compounds, the best method is to hydrolyze halogenated toluene with substituent groups to prepare benzaldehyde with substituent groups, and then prepare a target product by nitration. However, this preparation method has the following disadvantages: (1) The benzaldehyde with substituent is directly nitrified, and the aldehyde group is inevitably and partially oxidized into carboxylic acid due to the oxidability of nitric acid; (2) Benzaldehyde with a substituent can drift out along with water vapor in the preparation process and is attached to a condenser and other positions, so that the system is blocked, and great potential safety hazards are brought to production; (3) The preparation of benzaldehyde with substituent groups requires cooling crystallization and solid-liquid separation, and has the advantages of multiple operation steps, long period and the like.
Aiming at the technical problems, the invention provides a preparation method of nitrobenzaldehyde, which is particularly suitable for preparing 2-chloro-4-fluoro-5-nitrobenzaldehyde, and the preparation method has the advantages of simple operation, high atom utilization rate, simple post-treatment, high yield, good product quality and high safety, and is particularly suitable for industrial application.
Disclosure of Invention
In order to solve the above technical problems, a first aspect of the present invention provides a method for preparing nitrobenzaldehyde, comprising the steps of:
(1) Nitration reaction: adding benzyl dichloride with substituent groups into the mixed solution of sulfuric acid and nitric acid, controlling the reaction temperature to be not higher than 60 ℃, and reacting for 1-10h;
(2) And (3) hydrolysis reaction: heating the reaction system to 60-120 ℃, reacting for 1-20h, and stopping reaction;
the structure of benzyl dichloride with substituent groups is shown as a formula I; the position of the substituent R is at least one of ortho-position, meta-position and para-position; the number of the substituent groups R is 1-5, and the substituent groups R are selected from at least one of hydrogen, alkyl and halogen;
in a preferred technical scheme of the invention, in the mixed solution of sulfuric acid and nitric acid, the mass ratio of sulfuric acid to nitric acid is (1-10): 1.
as a preferable technical scheme of the invention, the water content in the mixed solution of the sulfuric acid and the nitric acid is 0-20wt%.
As a preferable technical scheme, the molar ratio of the benzyl dichloride with the substituent groups to the nitric acid is 1: (1-1.25).
As a preferred technical scheme of the invention, the temperature of the nitration reaction is-50-40 ℃.
As a preferred technical scheme of the invention, the temperature of the hydrolysis reaction is 70-100 ℃.
As a preferable technical scheme of the invention, the heating rate of the hydrolysis reaction is not more than 2 ℃/min.
As a preferred technical scheme, the preparation method of the nitrobenzaldehyde also comprises post-treatment; the post-treatment comprises the following specific steps: reducing the temperature of the reaction system to below 10 ℃, then adding water, controlling the temperature of the system to be not higher than 0 ℃, and carrying out solid-liquid separation after the product is crystallized and separated out to obtain the catalyst.
In the preparation method of the nitrobenzaldehyde, the benzyl dichloride with the substituent is 2-chloro-4-fluoro-benzyl dichloride shown as a formula II;
the invention provides an application of nitrobenzaldehyde, which is prepared according to the preparation method of nitrobenzaldehyde and is applied to organic intermediates of medicines and pesticides.
Advantageous effects
The invention provides a preparation method of nitrobenzaldehyde, which takes benzyl dichloride with substituent groups as raw materials, and synthesizes target products in one step through nitration reaction and hydrolysis reaction, the reaction process does not need to be processed, and no organic solvent or organic matters are involved, and the method has the advantages of simple post-processing, high product purity, good yield, cleanness, environmental protection, simple operation, high atom utilization rate, high productivity, low cost and the like, is particularly suitable for preparing 2-chloro-4-fluoro-5-nitrobenzaldehyde, and is easy to realize industrialization.
Detailed Description
The technical features of the technical solutions provided by the present invention will be further clearly and completely described below with reference to the specific embodiments, and it should be apparent that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
It will be understood by those skilled in the art that, unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the prior art and will not be interpreted in an idealized or overly formal sense unless expressly so defined herein.
The words "preferred", "preferably", "more preferred", and the like, in the present invention, refer to embodiments of the invention that may provide certain benefits, under certain circumstances. However, other embodiments may be preferred, under the same or other circumstances. Furthermore, the recitation of one or more preferred embodiments does not imply that other embodiments are not useful, nor is it intended to exclude other embodiments from the scope of the invention.
In order to solve the above technical problems, a first aspect of the present invention provides a method for preparing nitrobenzaldehyde, comprising the steps of:
(1) Nitration reaction: adding benzyl dichloride with substituent groups into the mixed solution of sulfuric acid and nitric acid, controlling the reaction temperature to be not higher than 60 ℃, and reacting for 1-10h;
(2) And (3) hydrolysis reaction: heating the reaction system to 60-120 ℃, reacting for 1-20h, and stopping the reaction.
In a preferred embodiment, the method for preparing nitrobenzaldehyde comprises the following steps:
(1) Nitration reaction: adding benzyl dichloride with substituent groups into a mixed solution of sulfuric acid and nitric acid, controlling the reaction temperature to be not higher than 60 ℃, and reacting until the residual quantity of the benzyl dichloride with substituent groups is lower than 0.5%;
(2) And (3) hydrolysis reaction: heating the reaction system to 60-120 ℃, reacting until the residual amount of the nitration product of benzyl dichloride with substituent groups is less than 0.5%, and stopping the reaction;
the structure of the benzyl dichloride with the substituent group is shown as a formula I; the position of the substituent R is at least one of ortho-position, meta-position and para-position; the number of the substituent R is 1-5, and the substituent R is selected from at least one of hydrogen, alkyl and halogen;
in the present invention, the method for detecting the residual amount of the raw material is not particularly limited, and liquid chromatography, gas chromatography and the like can be mentioned.
Nitration reaction
In the invention, the nitration reaction is as follows: adding benzyl dichloride with substituent groups into the mixed solution of sulfuric acid and nitric acid, controlling the reaction temperature to be not higher than 60 ℃, and reacting until the residual quantity of the benzyl dichloride with substituent groups is lower than 0.5%.
In a preferred embodiment, in the mixed solution of sulfuric acid and nitric acid, the mass ratio of sulfuric acid to nitric acid is (1-10): 1.
in a more preferred embodiment, in the mixed solution of sulfuric acid and nitric acid, the mass ratio of sulfuric acid to nitric acid is not less than 2:1.
in a preferred embodiment, the mixed solution of sulfuric acid and nitric acid has a water content of 0 to 20wt%.
In a more preferred embodiment, the sulfuric acid is concentrated sulfuric acid with a mass fraction of 98%; the nitric acid is concentrated nitric acid, and the mass concentration of the nitric acid is 95%.
In the invention, the preparation method of the mixed solution of sulfuric acid and nitric acid comprises the following steps: under the ice-bath condition, adding sulfuric acid into a container, then slowly adding nitric acid, and controlling the temperature in the container to be not higher than 60 ℃.
In the invention, the molar ratio of the benzyl dichloride with substituent groups to the nitric acid is 1: (1-1.25).
In a preferred embodiment, the molar ratio of substituted benzyl dichloride to nitric acid is 1: (1-1.1).
In a more preferred embodiment, the molar ratio of substituted benzyl dichloride and nitric acid is 1:1.05.
in the invention, the temperature of the nitration reaction is-50-40 ℃.
In a preferred embodiment, the temperature of the nitration reaction is in the range from 20 to 40 ℃.
Hydrolysis reaction
In the invention, the hydrolysis reaction is as follows: heating the reaction system to 60-120 ℃, reacting until the residual quantity of the nitration product of the benzyl dichloride with the substituent is less than 0.5%, and stopping the reaction.
In a preferred embodiment, the temperature of the hydrolysis reaction is 70-100 ℃.
In a preferred embodiment, the rate of temperature increase of the hydrolysis reaction does not exceed 2 ℃/min.
In a more preferred embodiment, the rate of temperature increase of the hydrolysis reaction does not exceed 0.5 deg.C/min.
Post-treatment
In the invention, the preparation method of the nitrobenzaldehyde also comprises post-treatment; the post-treatment comprises the following specific steps: reducing the temperature of the reaction system to below 10 ℃, then adding water, controlling the temperature of the system to be not higher than 0 ℃, and carrying out solid-liquid separation after the product is crystallized and separated out to obtain the catalyst.
In a preferred embodiment, the post-treatment comprises the following specific steps: cooling the reaction system to 0-5 ℃, then slowly dripping water, controlling the temperature of the system to be not higher than 0 ℃, and carrying out solid-liquid separation after the product is crystallized and separated out to obtain the product; the amount of the water to be used is not particularly limited and is well known to those skilled in the art.
In the preparation method of the nitrobenzaldehyde, the benzyl dichloride with the substituent is 2-chloro-4-fluoro-benzyl dichloride shown as a formula II;
in the present invention, the source of the 2-chloro-4-fluoro-benzyl dichloride is not particularly limited, and it can be obtained by self-made and purchased.
In a preferred embodiment, the 2-chloro-4-fluoro-benzyl dichloride is obtained by homemade; the preparation method of the 2-chloro-4-fluoro-benzyl dichloride comprises the following steps: 2-chloro-4-fluorotoluene was added to a four-necked flask with thermometer, condenser, snorkel, and good stirring. After the high-pressure mercury lamp is started, chlorine gas is introduced into the system at 60-70 ℃. HCl gas is produced as a byproduct during the reaction, so that tail gas needs to be captured. The reaction temperature was controlled and the progress of the reaction was followed by HPGC. And (5) after the reaction is finished, turning off the high-pressure mercury lamp to stop illumination. After cooling to room temperature, nitrogen was bubbled through the system to remove residual chlorine. To obtain the crude product of the 2-chloro-4-fluoro-benzyl dichloride. And (3) carrying out reduced pressure rectification on the crude product, keeping the vacuum degree at 0.15kPa, and receiving the fraction at 60-61 ℃ to obtain the high-content 2-chloro-4-fluoro-benzyl dichloride.
The preparation method of the 2-chloro-4-fluoro-5-nitrobenzaldehyde comprises the following steps:
(1) Nitration reaction: adding 2-chloro-4-fluoro-benzyl dichloride into a mixed solution of sulfuric acid and nitric acid, controlling the reaction temperature to be not higher than 60 ℃, and reacting until the residual quantity of the 2-chloro-4-fluoro-benzyl dichloride is lower than 0.5%;
(2) And (3) hydrolysis reaction: heating the reaction system to 60-120 ℃, reacting until the residual amount of 2-chloro-4-fluoro-5-nitro-benzyl dichloride is lower than 0.5%, and stopping the reaction.
In a preferred embodiment, in the mixed solution of sulfuric acid and nitric acid, the mass ratio of sulfuric acid to nitric acid is not less than 2:1; the water content is 0-20wt%.
The inventor finds that the nitration reaction generates a part of water besides the nitration product, which is not beneficial to the nitration reaction, and the inventor can well solve the problem by controlling the water content in the mixed solution of the sulfuric acid and the nitric acid and the mass ratio of the sulfuric acid to the nitric acid, so that the nitration reaction can be carried out more thoroughly. The inventor believes that the possible reason is that at the nitration reaction temperature, sulfuric acid has water absorbability, and particularly concentrated sulfuric acid with the mass concentration of 98% is adopted, so that the sulfuric acid can be quickly combined with water to form stable hydrate, and the influence of free water on the reaction in a nitration reaction system is reduced, so that the reaction can be carried out more completely.
In a preferred embodiment, the molar ratio of 2-chloro-4-fluoro-benzyl dichloride and nitric acid is 1: (1-1.25); preferably 1:1.05.
in a preferred embodiment, the temperature of the nitration reaction is from-50 to 60 ℃.
During research, the inventor finds that the nitration system of the invention has a molar ratio of 2-chloro-4-fluoro-benzyl dichloride to nitric acid of 1: (1-1.1), when the reaction temperature is-50-60 ℃, side reaction is hardly generated, the atom utilization rate almost reaches 100%, and a product of hydrolysis cross reaction is not generated. The inventors considered that the possible reason is that, at a lower nitration temperature (below 60 ℃), the 5-nitro substitution product is preferentially produced because the halogen is an ortho-para-positioning group and the dichloromethyl is a meta-positioning group, and because the 3-position and the 5-position of the benzene ring are more difficult to perform first than the electrophilic aromatic substitution reaction due to the presence of chlorine and fluorine at the 2-position of the benzene ring; meanwhile, the molar ratio of the 2-chloro-4-fluoro-benzyl dichloride to the nitric acid is 1: (1-1.1), the concentration of the nitro group in the reaction system is continuously reduced along with the progress of the reaction, and the nitration reaction at the 3-position of the benzene ring is further inhibited, so that the selectivity of the nitro group is high under the condition, and almost no side reaction exists. In addition, at a reaction temperature of 60 ℃ or lower, the reaction point of the hydrolysis reaction is not reached, and at this temperature, the molecule is not converted from a normal state to an active state in which a chemical reaction easily occurs, and the hydrolysis reaction does not occur, and therefore, there is no cross product of the hydrolysis reaction.
In a preferred embodiment, the temperature of the hydrolysis reaction is 70-100 ℃.
In a preferred embodiment, the rate of temperature increase of the hydrolysis reaction does not exceed 2 ℃/min; preferably 0.5 deg.C/min.
The inventor finds that the temperature rise speed in the stage of heating for hydrolysis reaction after the nitration reaction of the system is finished is not suitable to be too fast, otherwise, the generated hydrogen chloride gas is greatly escaped to cause a safety problem. During the research, the inventor finds that the hydrolysis reaction has the best effect when the temperature is increased at a rate of 0.5 ℃/min.
In a more preferred embodiment, the process for the preparation of 2-chloro-4-fluoro-5-nitrobenzaldehyde comprises the steps of:
(1) Nitration reaction: adding 2-chloro-4-fluoro-benzyl dichloride into a mixed solution of sulfuric acid and nitric acid, controlling the reaction temperature to be not higher than 60 ℃, and reacting until the residual quantity of the 2-chloro-4-fluoro-5-nitrobenzaldehyde is lower than 0.5%;
(2) And (3) hydrolysis reaction: heating the reaction system to 70-100 ℃, reacting until the residual amount of 2-chloro-4-fluoro-5-nitro-benzyl dichloride is less than 0.5%, and stopping the reaction;
(3) And (3) post-treatment: cooling the reaction system to 0-5 ℃, then slowly dripping water, controlling the temperature of the system to be not higher than 0 ℃, and carrying out solid-liquid separation after the product is crystallized and separated out to obtain the product.
The invention provides an application of nitrobenzaldehyde, which is prepared according to the preparation method of nitrobenzaldehyde and is applied to organic intermediates of medicines and pesticides.
In a preferred embodiment, the 2-chloro-4-fluoro-5-nitrobenzaldehyde prepared by the preparation method can be applied to organic intermediates of medicines and pesticides.
The method takes 2-chloro-4-fluoro-benzyl dichloride as a raw material, and generates the 2-chloro-4-fluoro-5-nitrobenzaldehyde in one step by monitoring the reaction process and adjusting the reaction temperature, and a purified product can be obtained by low-temperature crystallization only by adding water. Compared with the conventional method, the preparation method has the advantages of no organic solvent and organic matter participation in the reaction process, simple post-treatment, no operation of high-temperature distillation, recrystallization and the like of the nitride, safety, environmental protection, high product purity, good yield, high atom utilization rate, low cost and easy realization of industrialization.
The present invention will be specifically described below by way of examples. It should be noted that the following examples are only for illustrating the present invention and should not be construed as limiting the scope of the present invention, and that the insubstantial modifications and adaptations of the present invention by those skilled in the art based on the above disclosure are still within the scope of the present invention.
In addition, the starting materials used are all commercially available, unless otherwise specified.
Examples
Example 1
Example 1 provides a method for preparing 2-chloro-4-fluoro-5-nitrobenzaldehyde, comprising the steps of:
(1) Preparing mixed acid: adding 102g of 98% sulfuric acid into a 1000ml beaker, carrying out ice bath outside the beaker, and slowly adding 51g of 65% nitric acid, wherein the internal temperature is not higher than 60 ℃;
(2) Nitration reaction: 153g of prepared mixed acid is put into a four-neck flask with a stirring paddle, a dropping funnel and a thermometer, the external bath of the four-neck flask is a low-temperature circulating bath heat-conducting oil bath, and the temperature of the oil bath is set to be 60 ℃; starting stirring, and dropwise adding 107.8g of 2-chloro-4-fluoro-benzyl dichloride into the four-neck flask through a dropping funnel; controlling the temperature in the four-neck flask to be 60 ℃ for nitration reaction; after the dropwise addition, monitoring the reaction progress through liquid chromatography, and when the 2-chloro-4-fluoro-benzyl dichloride residue is less than 0.5%, the total reaction time is about 3-6 hours after the reaction is finished;
(3) And (3) hydrolysis reaction: transferring the nitration reaction liquid into a three-neck flask with a thermometer, a stirring paddle, a condenser and a tail gas absorption device, heating by using a low-temperature circulating bath heat-conducting oil bath, and setting the initial water temperature of the oil bath to be 70 ℃; starting stirring, raising the oil bath temperature by 5 ℃ every 10 minutes, controlling the final bath temperature of the oil bath kettle to be 100 ℃, and carrying out hydrolysis reaction; monitoring the reaction progress through liquid chromatography in the reaction process, and finishing the reaction when the content of the 2-chloro-4-fluoro-5-nitrodichlorotoluene is less than 0.5%;
(4) And (3) post-treatment: cooling a three-neck flask with a thermometer, a stirring paddle and a dropping funnel by using a low-temperature circulating bath heat-conducting oil bath, and setting the bath temperature to be 0-5 ℃; starting stirring, starting a dropping funnel regulating valve, and slowly adding water into the hydrolysate; setting bath temperature at-5 deg.C, controlling crystallization internal temperature less than 0 deg.C, dropwise adding hydrolysate, maintaining at 0 deg.C, and crystallizing at low temperature; and transferring the crystallization reaction liquid into a suction filter funnel, and carrying out reduced pressure filtration to obtain 95.6g of 2-chloro-4-fluoro-5-nitrobenzaldehyde, wherein the detection content is 98%, and the molar yield is 92.06%. 1 H NMR(600MHz，CDCl3)δ：10.41(s，1H)，8.64(d，J＝8.0Hz，1H)，7.54(d，J＝9.8Hz，1H)。
Example 2
Embodiment 2 provides a method for preparing 2-chloro-4-fluoro-5-nitrobenzaldehyde, comprising the steps of:
(1) Preparing mixed acid: 204g of 98 percent sulfuric acid is added into a 1000ml beaker, the beaker is subjected to ice bath, 51g of 65 percent nitric acid is slowly added, and the internal temperature is not higher than 60 ℃;
(2) Nitration reaction: 255g of prepared mixed acid (204g of 98 percent sulfuric acid and 51g of 65 percent nitric acid) is put into a four-neck flask with a stirring paddle, a dropping funnel and a thermometer, the outer bath of the four-neck flask is a low-temperature circulating bath heat-conducting oil bath, and the temperature of the oil bath is set to be 40 ℃; starting stirring, and dropwise adding 107.8g of 2-chloro-4-fluoro-benzyl dichloride into the four-neck flask through a dropping funnel; controlling the temperature in the four-mouth flask to be 40 ℃ for nitration reaction; after the dropwise addition, monitoring the reaction progress through liquid chromatography, and when the 2-chloro-4-fluoro-benzyl dichloride residue is less than 0.5%, the total reaction time is about 3-6 hours after the reaction is finished;
(3) And (3) hydrolysis reaction: transferring the nitration reaction liquid into a three-neck flask with a thermometer, a stirring paddle, a condenser and a tail gas absorption device, heating by using a low-temperature circulating bath heat-conducting oil bath, and setting the initial water temperature of the oil bath to be 70 ℃; starting stirring, raising the oil bath temperature by 5 ℃ every 10 minutes, controlling the final bath temperature of the oil bath kettle to be 100 ℃, and carrying out hydrolysis reaction; monitoring the reaction progress through liquid chromatography in the reaction process, and finishing the reaction when the content of the 2-chloro-4-fluoro-5-nitrodichlorotoluene is less than 0.5%;
(4) And (3) post-treatment: the three-neck flask with a thermometer, a stirring paddle and a dropping funnel is cooled by a low-temperature circulating bath heat conducting oil bath, and the bath temperature is set to be 0-5 ℃. Starting stirring, starting a regulating valve of a dropping funnel, and slowly adding water into the hydrolysate; setting bath temperature at-5 deg.C, controlling crystallization internal temperature less than 0 deg.C, dropwise adding hydrolysate, maintaining at 0 deg.C, and crystallizing at low temperature; and transferring the crystallization reaction liquid to a suction filter funnel, and carrying out reduced pressure filtration to obtain 97g of 2-chloro-4-fluoro-5-nitrobenzaldehyde, wherein the detection content is 99%, and the molar yield is 94.36%.
Example 3
Embodiment 3 provides a method for preparing 2-chloro-4-fluoro-5-nitrobenzaldehyde, comprising the steps of:
(1) Preparing mixed acid: 204g of 98% sulfuric acid is added into a 1000ml beaker, the beaker is subjected to ice bath, 51g of 65% nitric acid is slowly added, and the internal temperature is not higher than 60 ℃;
(2) Nitration reaction: 255g of prepared mixed acid (204g of 98 percent sulfuric acid and 51g of 65 percent nitric acid) is put into a four-neck flask with a stirring paddle, a dropping funnel and a thermometer, the outer bath of the four-neck flask is a low-temperature circulating bath heat-conducting oil bath, and the temperature of the oil bath is set to be 60 ℃; starting stirring, and dropwise adding 107.8g of 2-chloro-4-fluoro-benzyl dichloride into the four-neck flask through a dropping funnel; controlling the temperature in the four-neck flask to be 60 ℃ for nitration reaction; after the dropwise addition, monitoring the reaction progress through liquid chromatography, and when the 2-chloro-4-fluoro-benzyl dichloride residue is less than 0.5%, the total reaction time is about 3-6 hours after the reaction is finished;
(3) And (3) hydrolysis screening: transferring the nitration reaction liquid into a three-neck flask with a thermometer, a stirring paddle, a condenser and a tail gas absorption device, heating by using a low-temperature circulating bath heat-conducting oil bath, and setting the initial water temperature of the oil bath to be 70 ℃; stirring is started, the oil bath temperature is raised by 5 ℃ every 10 minutes, the final bath temperature of the oil bath kettle is controlled to be 100 ℃, and hydrolysis reaction is carried out. Monitoring the reaction progress through liquid chromatography in the reaction process, and finishing the reaction when the content of the 2-chloro-4-fluoro-5-nitrodichlorotoluene is less than 0.5%;
(4) And (3) post-treatment: the three-neck flask with a thermometer, a stirring paddle and a dropping funnel is cooled by a low-temperature circulating bath heat conducting oil bath, and the bath temperature is set to be 0-5 ℃. And (4) starting stirring, opening a regulating valve of the dropping funnel, and slowly adding water into the hydrolysate. Setting bath temperature at-5 deg.C, controlling crystallization internal temperature less than 0 deg.C, dropwise adding hydrolysate, maintaining at 0 deg.C, and crystallizing at low temperature; and transferring the crystallization reaction liquid to a suction filter funnel, and carrying out reduced pressure filtration to obtain 96.5g of 2-chloro-4-fluoro-5-nitrobenzaldehyde, wherein the detection content is 97.5%, and the molar yield is 92.45%.
Example 4
Embodiment 4 provides a method for preparing 2-chloro-4-fluoro-5-nitrobenzaldehyde, comprising the steps of:
(1) Preparing mixed acid: adding 306g of 98% sulfuric acid into a 1000ml beaker, carrying out ice bath outside the beaker, and slowly adding 51g of 65% nitric acid, wherein the internal temperature is not higher than 20 ℃;
(2) Nitration reaction: 357g of prepared mixed acid (306g of 98 percent sulfuric acid and 51g of 65 percent nitric acid) is put into a four-neck flask with a stirring paddle, a dropping funnel and a thermometer, and the external bath of the four-neck flask is a low-temperature circulating bath heat-conducting oil bath with a set oil bath temperature of 20 ℃; starting stirring, and dropwise adding 107.8g of 2-chloro-4-fluoro-benzyl dichloride into the four-neck flask through a dropping funnel; the temperature in the four-neck flask is controlled at 20 ℃ to carry out nitration reaction. After the dropwise addition, monitoring the reaction progress through liquid chromatography, and when the 2-chloro-4-fluoro-benzyl dichloride residue is less than 0.5%, the total reaction time is about 3-6 hours after the reaction is finished;
(3) And (3) hydrolysis reaction: transferring the nitration reaction liquid into a three-neck flask with a thermometer, a stirring paddle, a condenser and a tail gas absorption device, heating by using a low-temperature circulating bath heat-conducting oil bath, and setting the initial water temperature of the oil bath to be 70 ℃; stirring is started, the oil bath temperature is raised by 5 ℃ every 10 minutes, the final bath temperature of the oil bath kettle is controlled to be 100 ℃, and hydrolysis reaction is carried out. Monitoring the reaction progress through liquid chromatography in the reaction process, and finishing the reaction when the content of the 2-chloro-4-fluoro-5-nitrodichlorotoluene is less than 0.5%;
(4) And (3) post-treatment: cooling a three-neck flask with a thermometer, a stirring paddle and a dropping funnel by using a low-temperature circulating bath heat-conducting oil bath, and setting the bath temperature to be 0-5 ℃; and starting stirring, starting a dropping funnel regulating valve, and slowly adding water into the hydrolysate. Setting bath temperature at-5 deg.C, controlling crystallization temperature to be less than 0 deg.C, dropwise adding hydrolysate, maintaining at 0 deg.C, and crystallizing at low temperature; and transferring the crystallization reaction liquid to a suction filter funnel, and carrying out reduced pressure filtration to obtain 97.6g of 2-chloro-4-fluoro-5-nitrobenzaldehyde, wherein the detection content is 99.1 percent, and the molar yield is 94.94 percent.
Example 5
Embodiment 5 provides a method for preparing 2-chloro-4-fluoro-5-nitrobenzaldehyde, comprising the steps of:
(1) Preparing mixed acid: adding 306g of 98% sulfuric acid into a 1000ml beaker, slowly adding 53.6g of 99% potassium nitrate into the beaker in an ice bath, and keeping the internal temperature not higher than 60 ℃;
(2) Nitration reaction: 359.6g of prepared mixed acid (306g of 98% sulfuric acid and 53.6g of 99% potassium nitrate) is put into a four-neck flask with a stirring paddle, a dropping funnel and a thermometer, the external bath of the four-neck flask is a low-temperature circulating bath heat-conducting oil bath, and the temperature of the oil bath is set to be 40 ℃; starting stirring, and dropwise adding 107.8g of 2-chloro-4-fluoro-benzyl dichloride into the four-neck flask through a dropping funnel; controlling the temperature in the four-mouth flask to be 40 ℃ for nitration reaction; after the dropwise addition, monitoring the reaction progress through liquid chromatography, and when the 2-chloro-4-fluoro-benzyl dichloride residue is less than 0.5%, the total reaction time is about 3-6 hours after the reaction is finished;
(3) And (3) hydrolysis reaction: transferring the nitration reaction liquid into a three-neck flask with a thermometer, a stirring paddle, a condenser and a tail gas absorption device, heating by using a low-temperature circulating bath heat-conducting oil bath, and setting the initial water temperature of the oil bath to be 70 ℃; starting stirring, raising the oil bath temperature by 5 ℃ every 10 minutes, controlling the final bath temperature of the oil bath kettle to be 100 ℃, and carrying out hydrolysis reaction; monitoring the reaction progress through liquid chromatography in the reaction process, and finishing the reaction when the content of the 2-chloro-4-fluoro-5-nitrodichlorotoluene is less than 0.5%;
(4) And (3) post-treatment: cooling in a three-neck flask with a thermometer, a stirring paddle and a dropping funnel by using a low-temperature circulating bath heat-conducting oil bath, and setting the bath temperature to be 0-5 ℃; starting stirring, starting a dropping funnel regulating valve, and slowly adding water into the hydrolysate; setting bath temperature at-5 deg.C, controlling crystallization temperature to be less than 0 deg.C, dropwise adding hydrolysate, maintaining at 0 deg.C, and crystallizing at low temperature; and transferring the crystallization reaction liquid to a suction filter funnel, and carrying out reduced pressure filtration to obtain 97g of 2-chloro-4-fluoro-5-nitrobenzaldehyde, wherein the detection content is 99%, and the molar yield is 94.36%.
Example 6
Embodiment 6 provides a method for preparing 2-chloro-4-fluoro-5-nitrobenzaldehyde, comprising the steps of:
(1) Preparing mixed acid: 102g of 98% sulfuric acid is added into a 1000ml beaker, the outside of the beaker is subjected to ice bath, 34.9g of 95% fuming nitric acid is slowly added, and the internal temperature is not higher than 60 ℃;
(2) Nitration reaction: 136.9g of prepared mixed acid (102g of 98 percent sulfuric acid and 34.9g of 95 percent fuming nitric acid) is put into a four-neck flask with a stirring paddle, a dropping funnel and a thermometer, the external bath of the four-neck flask is a low-temperature circulating bath heat-conducting oil bath, and the temperature of the oil bath is set to be 40 ℃; with stirring turned on, 107.8g of 2-chloro-4-fluoro-benzyl dichloride was added dropwise to the four-necked flask via a dropping funnel. Controlling the temperature in the four-mouth flask to be 40 ℃ for nitration reaction; after the dropwise addition, monitoring the reaction progress through liquid chromatography, and when the 2-chloro-4-fluoro-benzyl dichloride residue is less than 0.5%, the total reaction time is about 3-6 hours after the reaction is finished;
(3) And (3) hydrolysis reaction: transferring the nitration reaction liquid into a three-neck flask with a thermometer, a stirring paddle, a condenser and a tail gas absorption device, heating by using a low-temperature circulating bath heat-conducting oil bath, and setting the initial water temperature of the oil bath to be 70 ℃; starting stirring, raising the temperature of the oil bath by 5 ℃ every 10 minutes, controlling the final bath temperature of the oil bath kettle to be 100 ℃, and carrying out hydrolysis reaction; monitoring the reaction progress through liquid chromatography in the reaction process, and finishing the reaction when the content of the 2-chloro-4-fluoro-5-nitrodichlorotoluene is less than 0.5%;
(4) And (3) post-treatment: cooling a three-neck flask with a thermometer, a stirring paddle and a dropping funnel by using a low-temperature circulating bath heat-conducting oil bath, and setting the bath temperature to be 0-5 ℃; and (4) starting stirring, opening a regulating valve of the dropping funnel, and slowly adding water into the hydrolysate. Setting bath temperature at-5 deg.C, controlling crystallization temperature to be less than 0 deg.C, dropwise adding hydrolysate, maintaining at 0 deg.C, and crystallizing at low temperature; and transferring the crystallization reaction liquid into a suction filter funnel, and carrying out reduced pressure filtration to obtain 96.5g of 2-chloro-4-fluoro-5-nitrobenzaldehyde, wherein the detection content is 99%, and the molar yield is 93.87%.
Example 7
Embodiment 7 provides a method for preparing 2-chloro-4-fluoro-5-nitrobenzaldehyde, comprising the steps of:
(1) Preparing mixed acid: adding 306g of 93 percent sulfuric acid into a 1000ml beaker, carrying out ice bath outside the beaker, and slowly adding 34.9g of 95 percent fuming nitric acid, wherein the internal temperature is not higher than 60 ℃;
(2) Nitration reaction: putting 340.9g (306g of 93% sulfuric acid and 34.9g of 95% fuming nitric acid) of prepared mixed acid into a four-neck flask with a stirring paddle, a dropping funnel and a thermometer, wherein the external bath of the four-neck flask is a low-temperature circulating groove heat-conducting oil bath, and the temperature of the oil bath is set to be 40 ℃; starting stirring, and dropwise adding 107.8g of 2-chloro-4-fluoro-benzyl dichloride into the four-neck flask through a dropping funnel; the temperature in the four-neck flask is controlled at 40 ℃ to carry out nitration reaction. After the dropwise addition, monitoring the reaction progress through liquid chromatography, and when the 2-chloro-4-fluoro-benzyl dichloride residue is less than 0.5%, the total reaction time is about 3-6 hours after the reaction is finished;
(3) And (3) hydrolysis reaction: transferring the nitration reaction liquid into a three-neck flask with a thermometer, a stirring paddle, a condenser and a tail gas absorption device, heating by using a low-temperature circulating bath heat-conducting oil bath, and setting the initial water temperature of the oil bath to be 70 ℃; starting stirring, raising the temperature of the oil bath by 5 ℃ every 10 minutes, controlling the final bath temperature of the oil bath kettle to be 100 ℃, and carrying out hydrolysis reaction; monitoring the reaction progress through liquid chromatography in the reaction process, and finishing the reaction when the content of the 2-chloro-4-fluoro-5-nitrodichlorotoluene is less than 0.5%;
(4) And (3) post-treatment: cooling a three-neck flask with a thermometer, a stirring paddle and a dropping funnel by using a low-temperature circulating bath heat-conducting oil bath, and setting the bath temperature to be 0-5 ℃; starting stirring, starting a dropping funnel regulating valve, and slowly adding water into the hydrolysate; setting bath temperature at-5 deg.C, controlling crystallization temperature to be less than 0 deg.C, dropwise adding hydrolysate, maintaining at 0 deg.C, and crystallizing at low temperature; and transferring the crystallization reaction liquid into a suction filter funnel, and carrying out reduced pressure filtration to obtain 95.5g of 2-chloro-4-fluoro-5-nitrobenzaldehyde, wherein the detection content is 99% and the molar yield is 92.90%.
The foregoing examples are merely illustrative and serve to explain some of the features of the method of the present invention. The appended claims are intended to claim as broad a scope as is contemplated, and the examples presented herein are merely illustrative of selected implementations in accordance with all possible combinations of examples. Accordingly, it is applicants' intention that the appended claims are not to be limited by the choice of examples illustrating features of the invention. Where the claims recite a range of values, such ranges are intended to include all sub-ranges subsumed therein, and variations within the ranges are intended to be encompassed by the claims as appended hereto where possible.
Claims (9)
1. A preparation method of nitrobenzaldehyde is characterized by comprising the following steps:
(1) Nitration reaction: adding benzyl dichloride with substituent groups into the mixed solution of sulfuric acid and nitric acid, controlling the reaction temperature to be not higher than 60 ℃, and reacting for 1-10h;
(2) And (3) hydrolysis reaction: heating the reaction system to 60-120 ℃, reacting for 1-20h, and stopping the reaction;
the structure of the benzyl dichloride with the substituent group is shown as a formula I; the position of the substituent R is at least one of ortho-position, meta-position and para-position; the number of the substituent groups R is 1-5, and the substituent groups R are selected from at least one of hydrogen, alkyl and halogen;
2. the method for preparing nitrobenzaldehyde according to claim 1, wherein the mass ratio of sulfuric acid to nitric acid in the mixed solution of sulfuric acid and nitric acid is (1-10): 1.
3. the method for producing nitrobenzaldehyde according to claim 1, wherein said mixed solution of sulfuric acid and nitric acid contains water in an amount of 0 to 20wt%.
4. The method for preparing nitrobenzaldehyde according to claim 1, wherein said substituted benzyl dichloride and nitric acid are present in a molar ratio of 1: (1-1.25).
5. The process for preparing nitrobenzaldehyde according to claim 1, wherein the temperature of said nitration is between-50 ℃ and 40 ℃.
6. The process for the preparation of nitrobenzaldehyde according to claim 1 wherein the temperature of said hydrolysis reaction is between 70 ℃ and 100 ℃.
7. The process for preparing nitrobenzaldehyde according to claim 1, wherein the rate of temperature increase of said hydrolysis reaction does not exceed 2 ℃/min.
8. The method for producing nitrobenzaldehyde according to claim 1, wherein said method for producing nitrobenzaldehyde further comprises a post-treatment; the post-treatment comprises the following specific steps: reducing the temperature of the reaction system to below 10 ℃, then adding water, controlling the temperature of the system to be not higher than 0 ℃, and carrying out solid-liquid separation after the product is crystallized and separated out to obtain the catalyst.
9. The method for producing nitrobenzaldehyde according to any of claims 1 to 8, wherein said nitrobenzaldehyde is 2-chloro-4-fluoro-5-nitrobenzaldehyde and said substituted benzyl dichloride is 2-chloro-4-fluoro-benzyl dichloride.
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