CN111848406B - Preparation method of 2-chloro-4-fluoro-5-nitrobenzaldehyde - Google Patents
Preparation method of 2-chloro-4-fluoro-5-nitrobenzaldehyde Download PDFInfo
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- C07—ORGANIC CHEMISTRY
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- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
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- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
- C07C17/10—Preparation of halogenated hydrocarbons by replacement by halogens of hydrogen atoms
- C07C17/14—Preparation of halogenated hydrocarbons by replacement by halogens of hydrogen atoms in the side-chain of aromatic compounds
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- C07C45/42—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by hydrolysis
- C07C45/43—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by hydrolysis of >CX2 groups, X being halogen
Abstract
The invention belongs to the field of organic synthesis, and particularly relates to a preparation method of 2-chloro-4-fluoro-5-nitrobenzaldehyde. Introducing chlorine gas into 2-chloro-4-fluoro-toluene as a raw material under the irradiation of high-pressure ultraviolet light for chlorination reaction, hydrolyzing the obtained product under the action of a catalyst, performing nitration reaction after hydrolysis, and separating out 2-chloro-4-fluoro-5-nitrobenzaldehyde in ice water after nitration reaction. The method has the advantages of simple process, simple and convenient operation, mild reaction conditions, high product content, high raw material conversion rate, convenient and easily obtained raw materials, suitability for industrial production and the like.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a preparation method of 2-chloro-4-fluoro-5-nitrobenzaldehyde.
Background
2-chloro-4-fluoro-5-nitrobenzaldehyde is an important agricultural herbicide and an intermediate or raw material for medicines, and documents CN105777733, WO2016095768, WO9522547, US4913723, US4959098, WO8704049, WO2007036718 and the like report the same.
References relating to the synthesis of 2-chloro-4-fluoro-5-nitrobenzaldehyde are:
the synthesis route of 2-chloro-4-fluoro-5-nitrobenzaldehyde reported in the literature (patent JPS60152465) is as follows:
mainly comprises the following 3 steps: (1) 2-chloro-4-fluoro-toluene is used as an initial raw material and undergoes substitution reaction with bromine under the catalytic action of azobisisobutyronitrile to prepare 2-chloro-4-fluoro-dibromotoluene; (2) 2-chloro-4-fluoro-dibromotoluene is subjected to hydrolysis reaction in a 95% sulfuric acid system at 125 ℃, a certain amount of ice is added into the reaction system after the hydrolysis reaction is finished, and the precipitated crystals are subjected to washing, ether dissolution, anhydrous sodium sulfate drying, ether removal and the like for multiple times to obtain 2-chloro-4-fluoro-benzaldehyde; (3) 2-chloro-4-fluoro-benzaldehyde is subjected to nitration reaction in a mixed acid (sulfuric acid/nitric acid) system. After the reaction is finished, the mixture is slowly added into ice water, and after operations of filtering, washing, dissolving with diethyl ether, washing, drying with anhydrous sodium sulfate, removing diethyl ether and the like, the target product is obtained by washing with n-hexane. In the above preparation method, the total yield is about 63% (based on 2-chloro-4-fluorotoluene), and the preparation yield of 2-chloro-4-fluoro-benzaldehyde is 79% (based on 2-chloro-4-fluorotoluene); the preparation yield of 2-chloro-4-fluoro-5-nitrobenzaldehyde was 79% (based on 2-chloro-4-fluorobenzaldehyde).
The document (patent WO2007036718) reports that 2-chloro-4-fluoro-5-nitrobenzaldehyde is prepared by adding potassium nitrate solid in batches into a concentrated sulfuric acid solution of 2-chloro-4-fluorobenzaldehyde for nitration reaction. After the reaction, the reaction product was added to ice water, and the mixture was extracted with ethyl acetate, and the extract was concentrated to obtain 2-chloro-4-fluoro-5-nitrobenzaldehyde as a pale yellow oil with a yield of 90% (using 2-chloro-4-fluorobenzaldehyde).
The document (patent US4913723) reports that 2-chloro-4-fluorobenzaldehyde is nitrated with a mixed acid of fuming nitric acid and concentrated sulfuric acid by using dichloromethane as a solvent, then the reactant is added into ice water, and the oily substance obtained after the solvent is removed is 2-chloro-4-fluoro-5-nitrobenzaldehyde, with the yield being about 90% (based on 2-chloro-4-fluorobenzaldehyde).
The literature reports on the preparation of the intermediate 2-chloro-4-fluoro-benzaldehyde are mainly as follows:
the document (patent US4846875) uses N-bromosuccinimide (NBS) as a brominating agent, and 2-chloro-4-fluorotoluene undergoes bromination reaction in the presence of benzoyl peroxide to generate 2-chloro-4-fluoro-dibromotoluene; 2-chloro-4-fluoro-dibromotoluene is subjected to hydrolysis reaction in the presence of formic acid and concentrated sulfuric acid to generate 2-chloro-4-fluoro-benzaldehyde:
the document (patent CN106008346) reports that under the action of alkali and a reducing agent, 1-fluoro-3-chloro-4 iodobenzene and CO are directly subjected to reductive coupling by using palladium as a catalyst to prepare an intermediate 2-chloro-4-fluoro-benzaldehyde, wherein the yield is 83%:
liu et al (Chinese Journal of Chemistry,2014,32, 117-122.) use 2-chloro-4-fluoro-toluol as raw material, under the action of catalytic amount of iridium photosensitizer, oxidize 2-chloro-4-fluorobenzyl alcohol to obtain the target product with a yield of 92%:
Juan de M.
(European Journal of Organic Chemistry,2012,2, 260-263.) et al synthesized the target compound with a yield of 85% from 2-chloro-4-fluoro-ethyl benzoate (diisobutyl tert-butoxyaluminum hydride (LDBBA):
in the process of synthesizing 2-chloro-4-fluoro-5-nitrobenzaldehyde reported in the prior documents, bromine, diethyl ether and other raw materials which are difficult to operate and harm health and environment or reagents with higher price are used, and the operation is more complicated, the synthesis yield is lower, and the method is not suitable for industrial production.
Disclosure of Invention
The invention aims to provide a preparation method of 2-chloro-4-fluoro-5-nitrobenzaldehyde, which is simple to operate, safe, reliable, good in product quality, low in price and easy to obtain raw materials, high in yield and suitable for industrial production.
In order to achieve the purpose, the invention adopts the technical scheme that:
a preparation method of 2-chloro-4-fluoro-5-nitrobenzaldehyde comprises the steps of introducing chlorine into 2-chloro-4-fluoro-toluene serving as a raw material under the irradiation of high-pressure ultraviolet light to carry out chlorination reaction, hydrolyzing an obtained product under the action of a catalyst, carrying out nitration reaction after hydrolysis, and separating out 2-chloro-4-fluoro-5-nitrobenzaldehyde in ice water after nitration reaction.
And slowly adding the mixture after the nitration reaction into ice water to separate out a crude product of the 2-chloro-4-fluoro-5-nitrobenzaldehyde, and then filtering, washing and drying to obtain the 2-chloro-4-fluoro-5-nitrobenzaldehyde.
The chlorination reaction is to introduce chlorine into 2-chloro-4-fluoro-toluene under the irradiation of high-pressure ultraviolet light to perform chlorination reaction to obtain a crude product of 2-chloro-4-fluoro-dichlorotoluene, and then rectifying to obtain high-content 2-chloro-4-fluoro-dichlorotoluene; wherein the chlorination reaction temperature is selected from 0-155 ℃, the introduction amount of chlorine is 2.0-3.0 times of the mole number of the substrate 2-chloro-4-fluoro-dichlorotoluene, and the chlorine needs to be rapidly introduced to perform chlorination reaction with the substrate, and the common speed is 5-200 mL/min.
The change process of the chlorination process system composition is as follows: firstly, carrying out chlorination reaction on 2-chloro-4-fluorotoluene to generate 2-chloro-4-fluoro-monochlorotoluene; as the reaction proceeded, 2-chloro-4-fluoro-dichlorotoluene began to be produced. And (3) rectifying the crude product of the 2-chloro-4-fluoro-dichlorotoluene obtained after chlorination to obtain the high-content 2-chloro-4-fluoro-dichlorotoluene. The diameter of a rectifying tower column adopted in the rectifying process is 20mm, the length is 600mm, and a packing is a glass spring with the diameter of 4 mm.
The reaction does not need the participation of a solvent and the addition of other free radical initiators, and has the advantages of clean and environment-friendly process, simple operation, good safety and high conversion rate of raw materials. After the reaction is finished, the temperature of the reaction product is reduced to room temperature, and nitrogen is blown into the system to remove residual chlorine, so that a crude product of the 2-chloro-4-fluoro-dichlorotoluene is obtained. Rectifying the crude product of the 2-chloro-4-fluoro-dichlorotoluene to obtain the high-content 2-chloro-4-fluoro-dichlorotoluene.
The chlorination reaction temperature is 20-120 ℃, and the introduction amount of chlorine is 2.1-2.4 times of the mole number of the substrate 2-chloro-4-fluoro-dichlorotoluene.
The temperature of the further chlorination reaction is 30-100 ℃; further preferably, the temperature is 60 to 70 ℃.
The chlorination reaction process is carried out under the irradiation of an ultraviolet lamp without the participation of any solvent; the addition of any free radical initiating reagent is not needed, the method is safe and environment-friendly, and the process is clean and pollution-free; meanwhile, bromine is replaced by chlorine, so that the method is low in price, easy to operate and beneficial to industrialization.
The hydrolysis is to perform hydrolysis reaction on the rectified 2-chloro-4-fluoro-dichlorotoluene at 10-100 ℃ for 3-40 h under the action of a catalyst, stir the reaction product, cool the reaction product to 0-5 ℃ for solidification, and then filter, wash and dry the reaction product to obtain 2-chloro-4-fluorobenzaldehyde; wherein the adding amount of the catalyst is 0.1-20% (w/w) of a substrate 2-chloro-4-fluoro-dichlorotoluene, and the catalyst is N, N-dimethyl sulfoxide, tetrahydrofuran, methanol, ethanol, N, N-dimethylformamide, tetrabutylammonium bromide, benzyltriethylammonium chloride, tetrabutylammonium hydrogen sulfate, trioctylmethylammonium chloride, dodecyltrimethylammonium chloride or tetradecyltrimethylammonium chloride.
The optimal hydrolysis reaction temperature is 70-100 ℃; the catalyst is N, N-dimethyl sulfoxide, tetrahydrofuran, N, N-dimethylformamide, tetrabutylammonium bromide, benzyltriethylammonium chloride, tetrabutylammonium chloride or tetrabutylammonium hydrogen sulfate; the adding amount of the catalyst is 0.1-10% (w/w) of the substrate 2-chloro-4-fluoro-dichlorotoluene; the catalyst is N, N-dimethyl sulfoxide, tetrahydrofuran, N, N-dimethylformamide, tetrabutylammonium bromide, benzyltriethylammonium chloride, tetrabutylammonium chloride or tetrabutylammonium hydrogen sulfate.
The catalyst for the hydrolysis reaction is an organic solvent which can be dissolved in water and 2-chloro-4-fluorotoluene at the same time and does not react with any compound in the system, such as N, N-dimethyl sulfoxide, tetrahydrofuran, methanol, ethanol, N, N-dimethylformamide and the like, or a phase transfer catalyst, such as tetrabutylammonium bromide, benzyltriethylammonium chloride, tetrabutylammonium hydrogen sulfate, trioctylmethylammonium chloride, dodecyltrimethylammonium chloride and tetradecyltrimethylammonium chloride; the preferable catalyst is N, N-dimethyl sulfoxide, tetrahydrofuran, N, N-dimethylformamide, tetrabutylammonium bromide, benzyltriethylammonium chloride, tetrabutylammonium chloride and tetrabutylammonium hydrogen sulfate; further preferred are N, N-dimethyl sulfoxide, N-dimethylformamide, tetrabutylammonium bromide, benzyltriethylammonium chloride, tetrabutylammonium chloride, and further preferred catalysts are N, N-dimethyl sulfoxide, N-dimethylformamide, tetrabutylammonium bromide.
The addition amount of the optimized hydrolysis reaction catalyst is generally 0.1-10% of that of the substrate 2-chloro-4-fluoro-dichlorotoluene; further preferably, the addition amount is 0.5-5%; more preferably, the amount of the surfactant is 1% to 3%.
The hydrolysis reaction does not need to add a large amount of acid, only needs to add a small amount of water-soluble catalyst, and the catalyst is easy to remove through cooling, curing, washing and other operations of the product in the post-treatment process, thereby being beneficial to the improvement of the product quality.
The nitration reaction is carried out on the hydrolysate 2-chloro-4-fluorobenzaldehyde in a nitrate radical-containing system at the temperature of 0 to minus 30 ℃, and 2-chloro-4-fluoro-5-nitrobenzaldehyde is separated out in ice water at the temperature of 5 to minus 30 ℃ after the reaction; wherein, the nitrate radical-containing system is a system combining concentrated sulfuric acid and fuming nitric acid or nitrate; the usage amount of fuming nitric acid or nitrate is 1.05-1.2 times of the mole number of the 2-chloro-4-fluorobenzaldehyde; the dosage of the concentrated sulfuric acid is 5-30 times of the mass of the substrate 2-chloro-4-fluorobenzaldehyde.
The system is a system combining concentrated sulfuric acid and fuming nitric acid or a system combining concentrated sulfuric acid and potassium nitrate; the nitration reaction temperature is-30-0 ℃, and the precipitation temperature is-30-5 ℃.
The nitration reaction is carried out in a system combining concentrated sulfuric acid and fuming nitric acid or a system combining concentrated sulfuric acid and nitrate, but the system combining concentrated sulfuric acid and fuming nitric acid or the system combining concentrated sulfuric acid and potassium nitrate is preferred, and the addition amount of the concentrated sulfuric acid ensures that the reaction system has good transmission effect under stirring conditions so as to ensure the smooth reaction.
The nitration reaction is preferably carried out at a reaction temperature of-20 to-5 ℃ and more preferably at a reaction temperature of-20 to-10 ℃.
After the nitration reaction is finished, slowly adding the reaction system into an ice water mixture, and when 2-chloro-4-fluoro-5-nitrobenzaldehyde solid is separated out, the temperature is further preferably-15-0 ℃, and the further preferably-10-0 ℃.
The preparation process of the 2-chloro-4-fluoro-5-nitrobenzaldehyde does not need any solvent, and only filtration and water washing of a filter cake are needed in the later period, so that the operation of high-temperature distillation of the nitride is avoided, and the preparation method is safe and environment-friendly.
The content of the 2-chloro-4-fluoro-5-nitrobenzaldehyde obtained by the method can reach more than 98-99%.
The invention has the advantages that:
the preparation method is simple to operate, the solvent and other free radical initiators are not required to be added in the whole process, the safety is good, and the process is clean and environment-friendly; the intermediate 2-chloro-4-fluorobenzaldehyde and 2-chloro-4-fluoro-5-nitrobenzaldehyde are prepared without high-temperature operations such as heating distillation and the like, so that the process is safer; meanwhile, the target 2-chloro-4-fluoro-5-nitrobenzaldehyde has high purity, high yield and less side reaction, and has the advantages of safety, environmental protection, simple operation, high productivity, low cost, easy realization of industrial production and the like; further, the following steps are carried out:
the chlorination reaction is to inject chlorine into the 2-chloro-4-fluorotoluene at a certain speed under the irradiation of high-pressure ultraviolet light to carry out chlorination reaction, thus obtaining the 2-chloro-4-fluoro-dichlorotoluene. The reaction does not need the participation of a solvent and the addition of other free radical initiators, and has the advantages of clean and environment-friendly process, simple operation, good safety and high conversion rate of raw materials. After the reaction is finished, cooling the reactants to room temperature, and blowing nitrogen into the system to remove residual chlorine to obtain a crude product of the 2-chloro-4-fluoro-dichlorotoluene; rectifying the crude product of the 2-chloro-4-fluoro-dichlorotoluene to obtain high-content 2-chloro-4-fluoro-dichlorotoluene; meanwhile, bromine is replaced by chlorine, so that the method is low in price, easy to operate and beneficial to industrialization.
Detailed Description
The invention is further illustrated by the following examples, without limiting the scope of protection, which are intended to be covered by the present invention, by optimization of the chemical variables known to the skilled person, such as temperature, feed mixture ratio, etc., and by substitution of the phase transfer catalyst or of an organic solvent which is soluble in both water and 2-chloro-4-fluorotoluene during the hydrolysis.
The synthetic route of the invention is as follows:
(1) carrying out chlorination reaction on the 2-chloro-4-fluorotoluene under the irradiation of high-pressure ultraviolet lamp light to generate a crude product of the 2-chloro-4-fluoro-dichlorotoluene, and rectifying to obtain the high-content 2-chloro-4-fluoro-dichlorotoluene;
(2) under the action of a catalyst, 2-chloro-4-fluoro-dichlorotoluene is subjected to hydrolysis reaction, the reaction is finished, stirred, cooled and solidified, and filtered, washed and dried to obtain 2-chloro-4-fluorobenzaldehyde;
(3) carrying out nitration reaction on the 2-chloro-4-fluorobenzaldehyde in a system combining concentrated sulfuric acid and fuming nitric acid or a system combining concentrated sulfuric acid and nitrate, slowly adding the product into ice water to separate out a product, and carrying out operations such as filtering, washing, drying and the like to obtain the 2-chloro-4-fluoro-5-nitrobenzaldehyde. The synthetic route is as follows:
preparation of 2-chloro-4-fluoro-dichlorotoluene:
example 1:
145.0g (1.0mol) of 2-chloro-4-fluorotoluene are placed in a 250mL four-necked flask with thermometer, condenser, snorkel and good stirring and cooled to 0 ℃ in an ice bath. After a high-pressure ultraviolet lamp is started to illuminate (the wavelength is 400nm, 220V and 250W), chlorine with the concentration of 99.6 percent is introduced into the system at the flow rate of 20 mL/min. The byproduct HCl gas is generated in the reaction process, so that tail gas needs to be collected. The reaction is an exothermic process, so the temperature of the system is increased, the temperature is controlled to be between 0 and 10 ℃ in the whole process, and the HPGC tracks the progress of the reaction. When the content of the 2-chloro-4-fluorotoluene is less than 1.0 percent, stopping introducing the chlorine, and closing the high-pressure ultraviolet lamp to stop illumination. After cooling to room temperature, nitrogen was bubbled through the system to remove residual chlorine. 216.1g of crude product are obtained.
And (3) carrying out reduced pressure rectification on the crude product, keeping the vacuum degree at 0.15Kpa, and receiving a fraction at 60-61 ℃ to obtain 189.9g of 99.0% 2-chloro-4-fluoro-dichlorotoluene with the yield of 88.1% (calculated by 2-chloro-4-fluorotoluene).1H NMR(600MHz,CDCl3)δ：7.92(dd,J＝8.4,5.8Hz,1H),7.14–7.05(m,3H)。
Example 2:
the preparation of 2-chloro-4-fluoro-dichlorotoluene was carried out with the same feed amounts and operation as described in example 1, except that:
the chlorination temperature is 155 ℃, the chlorine gas introduction speed is changed to 100mL/min, and 217.1g of crude product is obtained; then, the reaction mixture was subjected to rectification under reduced pressure to obtain 185.6g of 99.0% 2-chloro-4-fluoro-dichlorotoluene in a yield of 86.1% (based on 2-chloro-4-fluorotoluene).
Example 3:
the preparation of 2-chloro-4-fluoro-dichlorotoluene was carried out with the same feed amounts and operation as described in example 1, except that:
the chlorination temperature is selected to be between 60 and 70 ℃, the chlorine gas introduction speed is changed to be 100mL/min, and then 215.0g of crude product is obtained; then, the reaction mixture was rectified under reduced pressure to obtain 197.0g of 99.0% 2-chloro-4-fluoro-dichlorotoluene in a yield of 91.3% (based on 2-chloro-4-fluorotoluene).
Preparation of 2-chloro-4-fluorobenzaldehyde:
the 2-chloro-4-fluoro-dichlorotoluene prepared in the above examples is further hydrolyzed to obtain 2-chloro-4-fluorobenzaldehyde, which specifically comprises the following steps:
example 4:
40.0g (0.185mol) of 2-chloro-4-fluoro-dichlorotoluene obtained in the above example, 60.0g of water and 1.0g of DMSO were taken out and put in a three-necked flask, and the mixture was stirred and warmed to reflux, followed by progress of the reaction by HPLC. After 5h, stopping stirring, standing for layering, and analyzing a colorless transparent oily substance on a lower layer to obtain qualified 2-chloro-4-fluoro-dichlorotoluene with the content of less than 0.5%. Reducing the stirring speed, and slowly cooling to 0-5 ℃. Filtering, washing with cold water, and oven drying to obtain white granular crystal 29.0g, with content of 99.5% and yield of 98.0% (2-chloro-4-fluoro-diChlorotoluene meter). Melting point: 59.8 ℃; 1H NMR (600MHz, CDCl)3)δ：10.40(s,1H),7.98(dd,J＝8.7,6.2Hz,1H),7.20(dd,J＝8.3,2.4Hz,1H),7.11(ddd,J＝8.0,5.2,1.9Hz,1H)。
Example 5:
the preparation of 2-chloro-4-fluorobenzaldehyde was carried out in the same manner as described in example 4 above, except that:
1.5g of DMF was selected as a catalyst, and the reaction time was 6 hours, whereby 29.0g of white granular crystals having a content of 99.2% and a yield of 97.9% (based on 2-chloro-4-fluoro-dichlorotoluene) were obtained.
Example 6:
the preparation of 2-chloro-4-fluorobenzaldehyde was carried out in the same manner as described in example 4 above, except that:
1.5g of tetrabutylammonium bromide is selected as the catalyst, the reaction temperature is 70 ℃, and the reaction time is 15 h. 29.1g of white granular crystals were obtained, the content of which was 99.0% and the yield of which was 98.1% (based on 2-chloro-4-fluoro-dichlorotoluene).
Example 7:
the preparation of 2-chloro-4-fluorobenzaldehyde was carried out in the same manner as described in example 4 above, except that:
5g of methanol is selected as the catalyst, the reaction temperature is 20 ℃, and the reaction time is 37 h. 28.9g of white granular crystals were obtained, the content of which was 99.0% and the yield of which was 97.5% (based on 2-chloro-4-fluoro-dichlorotoluene).
Example 8:
the preparation of 2-chloro-4-fluorobenzaldehyde was carried out in the same manner as described in example 4 above, except that:
10.0g of DMSO was selected as the catalyst, and the reaction time was 2.5 hours. 28.6g of white granular crystals were obtained, the content of which was 98.7% and the yield of which was 96.0% (based on 2-chloro-4-fluoro-dichlorotoluene).
Preparation of 2-chloro-4-fluoro-5-nitrobenzaldehyde:
the 2-chloro-4-fluorobenzaldehyde prepared according to the above embodiments is subjected to nitration reaction to obtain 2-chloro-4-fluoro-5-nitrobenzaldehyde, specifically:
example 9:
30.0g of concentrated sulfuric acidAdding into a three-mouth bottle, and cooling by cold bath; at a temperature below 5 ℃, 8.0g (78.3mmol) KNO3Slowly adding the mixture into the solution in batches, and violently stirring the mixture to completely dissolve the mixture to form a colorless transparent solution A; adding 45g of concentrated sulfuric acid into a three-neck bottle, and cooling by a cold bath; 10.6g (66.5mmol) of 2-chloro-4-fluorobenzaldehyde are added slowly in portions to this at below 5 ℃ and stirred vigorously to dissolve them completely, giving a colorless or pale yellow transparent solution B. And (3) cooling the solution B to-10 to-15 ℃, slowly dripping the solution A into the solution B under a good stirring condition, keeping the temperature of the whole nitration process not higher than-10 ℃, continuing to stir for 1h after dripping is finished, slowly increasing the temperature to 20 ℃ (the temperature rise rate is not higher than 15 ℃/h), continuing to stir for 2h at 20 ℃, and finishing the reaction.
The reaction solution was cooled to below-15 ℃ and slowly added dropwise to 40.0g of ice water. The heat release amount in the process is large, and the temperature is not higher than 0 ℃. After the dropwise addition, the mixture is filtered at the temperature of below 15 ℃, filter cakes are washed by ice water and dried to obtain 12.6g of white crystal 2-chloro-4-fluoro-5-nitrobenzaldehyde with the content of 99.0 percent and the yield of 92.1 percent. Melting point: 42.0 ℃;1H NMR(600MHz,CDCl3):δ10.41(s,1H),8.64(d,J＝8.0Hz,1H),7.54(d,J＝9.8Hz,1H)。
example 10:
the preparation of 2-chloro-4-fluoro-5-nitrobenzaldehyde was carried out in the same manner as described in example 9 above, except that:
75.0g of concentrated sulfuric acid is added into a three-neck flask, the temperature is reduced by a cold bath, 10.6g (66.5mol) of 2-chloro-4-fluorobenzaldehyde is slowly added into the three-neck flask in batches at the temperature below 5 ℃, and the mixture is stirred vigorously to be completely dissolved to form colorless or light yellow transparent solution. And continuously cooling the solution to-10 to-15 ℃, dropwise adding 5.2g (80.0mmol) of fuming nitric acid into the system under a good stirring condition, keeping the temperature of the dropwise adding nitration process not higher than-10 ℃, continuously stirring for 1h after the dropwise adding is finished, slowly heating the solution to the room temperature of 20 ℃ (the heating rate is not higher than 15 ℃/h), continuously stirring for 2h at the temperature of 20 ℃, and finishing the reaction.
The reaction solution was cooled to below-15 ℃ and slowly added dropwise to 40.0g of ice water. The heat release amount in the process is large, and the temperature is not higher than 0 ℃. After the dropwise addition, the mixture is filtered at the temperature of below 15 ℃, filter cakes are washed by ice water and dried to obtain 12.4g of white crystal 2-chloro-4-fluoro-5-nitrobenzaldehyde with the content of 98.6 percent and the yield of 90.6 percent.
Example 11:
the preparation of 2-chloro-4-fluoro-5-nitrobenzaldehyde was carried out in the same manner as described in example 9 above, except that:
the temperature of the nitration process is not higher than-25 ℃. After the reaction is finished, water is added for dilution, and the temperature is not higher than-5 ℃. To obtain white crystal 2-chloro-4-fluoro-5-nitrobenzaldehyde 12.6g with the content of 98.4% and the yield of 91.1%.
Example 12:
the preparation of 2-chloro-4-fluoro-5-nitrobenzaldehyde was carried out in the same manner as described in example 9 above, except that:
the temperature of the nitration process is not higher than 0 ℃. After the reaction is finished, water is added to dilute the mixture at a temperature not higher than 0 ℃. To obtain white crystal 2-chloro-4-fluoro-5-nitrobenzaldehyde 12.1g with the content of 97.0 percent and the yield of 88.1 percent.
The above-mentioned embodiments are preferred applications of the present invention, but not intended to limit the invention in any way. In practice, the invention can be modified and practiced in different but equivalent manners apparent to those skilled in the art having the benefit of the teachings herein.
Claims (2)
1. A preparation method of 2-chloro-4-fluoro-5-nitrobenzaldehyde is characterized in that 2-chloro-4-fluoro-toluene is taken as a raw material, chlorine is introduced under the irradiation of high-pressure ultraviolet light for chlorination reaction, the obtained product is hydrolyzed under the action of a catalyst, nitration reaction is carried out after hydrolysis, and 2-chloro-4-fluoro-5-nitrobenzaldehyde is separated out in ice water after nitration reaction;
slowly adding the mixture after the nitration reaction into ice water to separate out a crude product of the 2-chloro-4-fluoro-5-nitrobenzaldehyde, and then filtering, washing and drying to obtain the 2-chloro-4-fluoro-5-nitrobenzaldehyde;
the chlorination reaction is to introduce chlorine into the 2-chloro-4-fluoro-toluene under the irradiation of high-pressure ultraviolet light to perform chlorination reaction to obtain a crude product of the 2-chloro-4-fluoro-dichlorotoluene, the HPGC tracks the reaction progress, when the content of the 2-chloro-4-fluoro-toluene is less than 1.0%, the introduction of the chlorine is stopped, and the high-pressure ultraviolet lamp is turned off to stop illumination; then rectifying to obtain high-content 2-chloro-4-fluoro-dichlorotoluene; wherein the chlorination reaction temperature is selected from 60-70 ℃; the hydrolysis is to perform hydrolysis reaction on the rectified 2-chloro-4-fluoro-dichlorotoluene at 70-100 ℃ for 3-40 h under the action of a catalyst, stir the reaction product, cool the reaction product to 0-5 ℃ for solidification, and then filter, wash and dry the reaction product to obtain 2-chloro-4-fluorobenzaldehyde; wherein the adding amount of the catalyst is 0.1-10% (w/w) of substrate 2-chloro-4-fluoro-dichlorotoluene, and the catalyst is dimethyl sulfoxide, tetrahydrofuran, N, N-dimethylformamide, tetrabutylammonium bromide, benzyltriethylammonium chloride, tetrabutylammonium hydrogen sulfate, trioctylmethylammonium chloride, dodecyltrimethylammonium chloride or tetradecyltrimethylammonium chloride;
the nitration reaction is carried out on a hydrolysate 2-chloro-4-fluorobenzaldehyde in a nitrate radical-containing system at the temperature of-30-0 ℃, and 2-chloro-4-fluoro-5-nitrobenzaldehyde is separated out in ice water at the temperature of-30-5 ℃ after the nitration reaction; wherein, the nitrate radical-containing system is a system combining concentrated sulfuric acid and fuming nitric acid or nitrate; the usage amount of fuming nitric acid or nitrate is 1.05-1.2 times of the mole number of the 2-chloro-4-fluorobenzaldehyde; the dosage of the concentrated sulfuric acid is 5-30 times of the mass of the substrate 2-chloro-4-fluorobenzaldehyde.
2. The process for producing 2-chloro-4-fluoro-5-nitrobenzaldehyde according to claim 1, wherein the system is a system of concentrated sulfuric acid and fuming nitric acid or a system of concentrated sulfuric acid and potassium nitrate; the nitration reaction temperature is-20 to-10 ℃, and the precipitation temperature is-10 to 0 ℃.
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