CN110803992B

CN110803992B - Preparation method of 3-nitro-4-fluoroacetophenone acetate

Info

Publication number: CN110803992B
Application number: CN201911180559.6A
Authority: CN
Inventors: 陈剑戈; 李斌峰; 苑可
Original assignee: JIMING PHARMATECH (SUZHOU) Ltd
Current assignee: JIMING PHARMATECH (SUZHOU) Ltd
Priority date: 2019-11-27
Filing date: 2019-11-27
Publication date: 2022-06-24
Anticipated expiration: 2039-11-27
Also published as: CN110803992A

Abstract

The invention discloses a method for preparing 3-nitro-4-fluoroacetate by using a microreactor, belonging to the technical field of organic synthesis, wherein the microreactor comprises a precooling module and a mixing module, and the method specifically comprises the following steps: (1) preparing raw materials: preparing a mixed solution of 4-fluorophenylacetate and concentrated sulfuric acid and a nitric acid solution; (2) pre-cooling: cooling the pre-cooling module and the mixing module to the reaction temperature in advance, and then respectively adding a mixed solution of 4-fluoroacetearate and concentrated sulfuric acid and a nitric acid solution into different pre-cooling modules; (3) mixing: after the precooling of the raw materials is finished, adding the raw materials into a mixing module for mixing reaction; (4) quenching and post-treatment. The method can effectively control the heat release problem of the nitration reaction and has high safety; and 3-nitro-4-fluoroacetoacetate can be prepared with high selectivity, the conversion rate of the 4-fluoroacetoacetate can reach 98.4%, and the selectivity can reach 99: 1.

Description

Preparation method of 3-nitro-4-fluoroacetoacetate

Technical Field

The invention belongs to the technical field of organic matter synthesis, and particularly relates to a preparation method of 3-nitro-4-fluoroacetoacetate.

Background

The dihydronaphthyridine compounds are kinase inhibitors for treating or preventing diseases such as gastrointestinal stromal tumor, acute myelogenous leukemia and systemic hypertrophy and hyperplasia. While 3-nitro-4-fluoroacetophenone acetate is an important intermediate in the construction of dihydronaphthyridine compounds, the method for synthesizing 3-nitro-4-fluoroacetophenone acetate is complex and is not reported in any literature.

A method for obtaining ethyl 3-nitro-4-fluorophenylacetate by nitration reaction using ethyl 4-fluorophenylacetate as a raw material is disclosed in the literature (Synthesis of azo-fluoro-catalyst and phosphor-catalysis of azo-fluoro-catalyst. M.Kuse et al tetrahedron,2005,61,5754-5762), and the specific preparation process is the nitration reaction carried out in a traditional reaction bottle. The nitration reaction has the outstanding characteristics of strong exothermicity, concentrated exothermicity and huge safety risk. The removal of heat is one of the outstanding problems in controlling the nitration reaction in conventional reactors. In addition, the nitration reaction of aromatic hydrocarbons has problems of multiple nitration, poor selectivity, and the like. We repeated experiments according to literature conditions, in a 200g scale reaction, the raw material was only converted to 78%, the residue was more, and the selectivity of the reaction was poor, the ratio of ethyl 2-nitro-4-fluorophenylacetate to ethyl 3-nitro-4-fluorophenylacetate isomers was 31: 69. this brings great difficulty to the separation of the target product and also makes it difficult to realize mass production.

Because the ortho-positioning effects of fluorine and methylene are relatively close, the high-purity ortho-nitronitration product is difficult to obtain by the traditional nitration process. The literature (Aluminum Chloride Catalyzed Nitration of Aromatics with Sodium Nitrate/chlorotrimethyl aniline A. olah et al Synthesis,1994,1, 468-469.) Aluminum trichloride Catalyzed the Nitration of fluorobenzene, the ratio of o-p-nitrobenzophenone being: 16: 84, the selectivity of the nitration reaction is poor even when catalyzed by the catalyst. The literature (Aromatic sub-simulation.48. boron trifluoride catalyzed nitration of Aromatic with silver nitrate in acidic solution. George A. olah et al. journal of Organic Chemistry,1981,46, 3533-: the method comprises the following steps: the proportion of p-nitrofluorobenzene is as follows: 27: 1: 72, even if the nitration is catalyzed, the nitration reaction is poor in selectivity. The literature (patent and selective CC chemoattractant 1antagonists of branched with carbon-13, carbon-14, and tertiary, Bachir Latli et al, journal of branched compounds and radiopharmaceuticals,2018,61, 764) nitration of fluorobenzene under trifluoroacetic anhydride/nitric acid conditions, the ratio of ortho-to-nitrofluorobenzene being 12: 88, poor selectivity.

The micro-reactor can well solve the problems of poor heat release and selectivity of the nitration reaction in the traditional reactor. Microreactors are three-dimensional structural elements fabricated by microfabrication techniques for carrying out chemical reactions, and generally comprise small channels (10 μm to 3.0mm in diameter) through which fluids flow and in which desired reactions take place. The micro-reactor reaction channel is extremely fine, the specific surface area of fluid in the channel is far larger than that of the traditional reaction kettle, and the micro-channel has extremely strong heat exchange capability. Because the reaction material retention in the microchannel is very small, the heat exchange capability is strong, thereby effectively controlling the heat release of the reaction and improving the reaction safety. In addition, the microchannel has strong heat exchange capacity, can accurately control the reaction temperature, effectively avoids the problem of local overheating caused by nonuniform heat transfer of reaction liquid, avoids side reactions and improves the selectivity of the reaction. The micro-reactor can well solve the problems of poor safety and poor selectivity of the nitration reaction.

The chinese patent application CN102432471A (a method for performing chlorobenzene nitro reaction by using a microchannel reactor) uses nitric acid, sulfuric acid, water, and chlorobenzene as starting materials, performs nitro reaction in the microchannel reactor, uses a mixed acid of nitric and sulfuric acid as a nitrating agent, controls the molar ratio of nitric acid and sulfuric acid to be 1:1-1:10, the molar ratio of chlorobenzene and nitric acid to be 1:1-1:2, and controls the reaction temperature and the reaction time, so that the final conversion rate of chlorobenzene can reach 96.5%, and the ratio of ortho-para nitrochlorobenzene is greater than 0.6.

The Chinese patent application CN106316859A (a method for synthesizing 2, 4-dichloro-3, 5-dinitrobenzotrifluoride in a microreactor) adds a nitrating agent consisting of raw materials of 2, 4-dichlorobenzotrifluoride, concentrated sulfuric acid and concentrated nitric acid into the microreactor to prepare the 2, 4-dichloro-3, 5-dinitrobenzotrifluoride through nitration reaction, compared with the traditional synthesis method, the reaction time is greatly reduced, the conversion rate of the 2, 4-dichlorobenzotrifluoride is more than 97 percent, the production efficiency is obviously improved, and the yield of the 2, 4-dichloro-3, 5-dinitrobenzotrifluoride is 40 percent. The Chinese patent application CN109970566A (a method for synthesizing a 1, 3-dinitro halogenobenzene compound) takes a halogenobenzene compound as a raw material and mixed acid of nitric acid and sulfuric acid as a nitrating agent, firstly carries out a first nitration reaction in a first-stage continuous flow microreactor to obtain a mononitro halogenobenzene compound, then introduces the mononitro halogenobenzene compound into a second-stage continuous flow microreactor to carry out a second nitration reaction, finally recycles second waste acid generated by the second nitration reaction into the first-stage continuous flow microreactor to carry out a third nitration reaction, and repeatedly carries out the second nitration reaction and the third nitration reaction to obtain the 1, 3-dinitro halogenobenzene compound. However, these two patents are primarily directed to the preparation of dinitro compounds and are not suitable for the preparation of monosubstituted 3-nitro-4-fluoroacetophenonates.

The method of nitration reaction using a microreactor as set forth in the above patent is not suitable for the preparation of 3-nitro-4-fluoroacetate from 4-fluoroacetoacetate, and the present invention proposes for the first time the preparation of 3-nitro-4-fluoroacetate using a microreactor starting from 4-fluoroacetoacetate.

Disclosure of Invention

The technical problems to be solved by the invention are that the method for preparing 3-nitro-4-fluoroacetate from 4-fluoroacetate in the prior art has the technical problems of low raw material conversion rate, poor spatial position selectivity and the like.

In order to solve the technical problem, the invention provides a method for preparing 3-nitro-4-fluoroacetophenone acetate by using a microreactor, wherein the microreactor comprises a precooling module and a mixing module, and the preparation method specifically comprises the following steps:

(1) preparing raw materials: preparing a mixed solution of 4-fluorophenylacetate and concentrated sulfuric acid and a nitric acid solution; wherein the concentrated sulfuric acid is 98% concentrated sulfuric acid by mass concentration, and the nitric acid is 69% nitric acid by mass concentration.

(2) Pre-cooling: cooling the pre-cooling module and the mixing module to the reaction temperature in advance, and then respectively adding a mixed solution of 4-fluoroacetophenone acetate and concentrated sulfuric acid and a nitric acid solution into different pre-cooling modules;

(3) mixing: after the precooling of the raw materials is finished, adding the raw materials into a mixing module for mixing reaction;

(4) quenching and post-treatment: after the reaction is finished, the reaction liquid enters a quenching tank for quenching, and extraction, alkali washing and water washing are carried out.

Further, the 3-nitro-4-fluoroacetophenone acetate is selected from one of methyl 3-nitro-4-fluoroacetophenote, ethyl 3-nitro-4-fluoroacetophenote, isopropyl 3-nitro-4-fluoroacetophenote and benzyl 3-nitro-4-fluoroacetophenote; correspondingly, the 4-fluorobenzene acetic ester is selected from one of 4-fluorobenzene acetic ester, 4-fluorobenzene acetic ester isopropyl ester and 4-fluorobenzene acetic ester benzyl ester. The method specifically comprises the following steps: preparing 3-nitro-4-fluorophenylmethyl acetate by taking 4-fluorophenylmethyl acetate as a raw material through nitration reaction; preparing 3-nitro-4-fluorophenylethyl acetate by taking 4-fluorophenylethyl acetate as a raw material through nitration reaction; preparing 3-nitro-4-fluorophenylacetic acid isopropyl ester by taking 4-fluorophenylacetic acid isopropyl ester as a raw material through nitration reaction; 4-fluorobenzenebenzyl acetate is used as a raw material, and 3-nitro-4-fluorobenzenebenzyl acetate is prepared through nitration reaction.

Further, the molar ratio of the 4-fluorobenzene acetate to the nitric acid is 1: 1.0-2.0.

Further, the molar ratio of 4-fluorophenylacetate to nitric acid is 1: 1.1.

Further, the preparation method of the mixed solution of 4-fluorophenylacetate and concentrated sulfuric acid in the step (1) comprises the following steps: 4-fluorobenzeneacetate is dissolved in concentrated sulfuric acid, and the dosage of the concentrated sulfuric acid relative to the 4-fluorobenzeneacetate is 1.1-4.0 mL/g.

Further, the amount of concentrated sulfuric acid used was 1.4mL/g relative to 4-fluoroacetophenoacetate.

And (3) in the step (2), the precooling temperature is 0-10 ℃, the temperatures of the precooling module and the mixing module are the same as the nitration reaction temperature, and the temperatures are controlled by an external heat exchanger. After the pre-cooling module is cooled to 0-10 ℃, the mixed solution of 4-fluoroacetophenone acetate and concentrated sulfuric acid and the nitric acid solution are respectively fed into two parallel pre-cooling modules through two constant flow pumps and cooled to 0-10 ℃.

Further, after the temperature of the mixing module in the step (3) is reduced to 0-10 ℃, the pre-cooled mixed solution of 4-fluoroacetophenone acetate and concentrated sulfuric acid and nitric acid solution enter the mixing module through the pre-cooling module to perform mixing reaction. The flow rate of the mixed solution of 4-fluoroacetophenone acetate and concentrated sulfuric acid was 9 to 18mL/min, and further, 15 mL/min. The feed flow rate ratio of the mixed solution of 4-fluorophenylacetate and concentrated sulfuric acid to the nitric acid solution was 6-3:1, and further, 5.7: 1. The reaction residence time is 20 to 80s, further 30 to 50 s.

In the invention, 4-fluorophenylacetate and concentrated sulfuric acid solution are mixed in advance and then mixed with concentrated sulfuric acid solution, and the adding rate of each solution is adjusted, so that the reaction speed can be better controlled; meanwhile, the speed of one solution needs to be synchronously adjusted to ensure that reactants can react according to the molar ratio close to 1:1, so that materials are fully utilized, and the waste of the materials can be reduced.

The invention takes 4-fluoroacetophenone acetate and concentrated nitric acid as raw materials, takes concentrated sulfuric acid as a catalyst, and utilizes a microreactor to carry out nitration reaction to prepare the 3-nitro-4-fluoroacetophenone acetate. Pumping concentrated sulfuric acid solution of 4-fluoroacetophenone acetate and nitric acid into a microreactor through a constant flow pump, precooling the microreactor to a reaction temperature through a precooling module, and then entering a mixing module to perform nitration reaction to obtain the 3-nitro-4-fluoroacetophenone acetate. According to the invention, by controlling the molar ratio of the 4-fluoroacetearate to the nitric acid and the dosage of the concentrated sulfuric acid, mixing the 4-fluoroacetearate and the concentrated sulfuric acid together in advance, and then mixing the mixture with the nitric acid, the rapid heat dissipation in the chemical reaction process can be effectively avoided, and the safety of the reaction is improved.

Compared with the prior art, the method for preparing the 3-nitro-4-fluoroacetophenone acetate by utilizing the microreactor has the following advantages:

1. can effectively control the heat release problem of the nitration reaction and has high safety.

2. The difference of the ortho-position effects of fluorine and methylene can be distinguished with high selectivity to prepare the 3-nitro-4-fluoroacetate, the conversion rate of the raw material 4-fluoroacetate can reach 98.4%, and the ortho-position and meta-position selectivity can reach 99; 1.

3. compared with the traditional reaction system reported in the literature, the reaction time is greatly shortened, the productivity is obviously improved, and the large-scale production can be carried out.

Drawings

FIG. 1: chemical structural general formula of dihydronaphthyridine compounds

FIG. 2: chemical structural formula of 3-nitro-4-fluorophenylacetic acid ethyl ester

FIG. 3: chemical reaction formula for preparing 3-nitro-4-fluoroacetate by taking 4-fluoroacetate as raw material

FIG. 4: scheme of nitration reaction

Detailed Description

The technical scheme of the invention is explained in detail through the figures and the specific embodiments of the specification.

Example 1

(1) Preparing raw materials: 200g of ethyl 4-fluorophenylacetate was dissolved in 280mL of 98% sulfuric acid for further use. 79mL of 69% nitric acid was used.

(2) Pre-cooling: and cooling the pre-cooling module and the mixing module to 0-10 ℃. Pumping the sulfuric acid solution and the nitric acid solution of the 4-fluorophenylethyl acetate into two parallel precooling modules by two constant flow pumps, and cooling to 0-10 ℃.

(3) Mixing: after the precooling of the raw materials is finished, the raw materials enter a mixing module for mixing reaction, the flow rate of the mixed solution of the 4-fluorophenylethyl acetate and the concentrated sulfuric acid is set to be 15mL/min, the flow rate of the nitric acid is 2.63mL/min, and the mixed solution is reacted in the mixing module for 42 s.

(4) Quenching and post-treatment: the reaction solution is quenched in a quenching tank, and 500mL of ethyl acetate and 500mL of water are stored in the quenching tank. And (3) quenching the reaction solution in a quenching tank, extracting, separating an organic phase, washing with a saturated sodium bicarbonate solution, washing with water, and concentrating to dry. The product after the reaction was designated as S1.

Examples 2 to 9

The preparation was carried out in the same manner as in example 1, except that the amount of the starting materials and some of the process parameters were changed to 200g of ethyl 4-fluorophenylacetate. Meanwhile, in order to ensure that the mixed solution of the 4-fluoroacetophenone acetate and the concentrated sulfuric acid entering the mixing module of the microreactor and the nitric acid solution can completely participate in the reaction, the flow rate is changed as required. The product after the reaction is marked as S2-S9.

The present invention also provides an example of preparing 3-nitro-4-fluoroacetoacetate from other 4-fluoroacetoacetates to demonstrate that the technical solution of the present invention has broader applicability, as shown in examples 10-11 below.

Example 10

(1) Preparing raw materials: 185g of methyl 4-fluorophenylacetate was dissolved in 280mL of 98% sulfuric acid for further use. 79mL of 69% nitric acid was used.

(2) Pre-cooling: and cooling the pre-cooling module and the mixing module to 0-10 ℃. Pumping the sulfuric acid solution and the nitric acid solution of the 4-fluorophenylmethyl acetate into two parallel precooling modules by two constant flow pumps to be cooled to 0-10 ℃.

(3) Mixing: after the precooling of the raw materials is finished, the raw materials enter a mixing module for mixing reaction, the flow rate of the mixed solution of the methyl 4-fluorophenylacetate and the concentrated sulfuric acid is set to be 14.8mL/min, the flow rate of the nitric acid is 2.63mL/min, and the mixed solution is reacted in the mixing module for 42 s.

(4) Quenching and post-treatment: the reaction solution is quenched in a quenching tank, and 500mL of ethyl acetate and 500mL of water are stored in the quenching tank. And (3) quenching the reaction solution in a quenching tank, extracting, separating an organic phase, washing with a saturated sodium bicarbonate solution, washing with water, and concentrating to dry. The product after the reaction was designated as S10.

Example 11

(1) Preparing raw materials: 216g of isopropyl 4-fluorophenylacetate was dissolved in 280mL of 98% sulfuric acid for use. 79mL of 69% nitric acid was used.

(2) Pre-cooling: and cooling the pre-cooling module and the mixing module to 0-10 ℃. Pumping the sulfuric acid solution and the nitric acid solution of the 4-fluorobenzene isopropyl acetate into two parallel precooling modules by two constant flow pumps to be cooled to 0-10 ℃.

(3) Mixing: after the precooling of the raw materials is finished, the raw materials enter a mixing module for mixing reaction, the flow rate of the mixed solution of the isopropyl 4-fluorophenylacetate and the concentrated sulfuric acid is set to be 15.2mL/min, the flow rate of the nitric acid is 2.63mL/min, and the mixed solution is reacted in the mixing module for 42 s.

(4) Quenching and post-treatment: the reaction solution is quenched in a quenching tank, and 500mL of ethyl acetate and 500mL of water are stored in the quenching tank. And (3) quenching the reaction solution in a quenching tank, extracting, separating an organic phase, washing with a saturated sodium bicarbonate solution, washing with water, and concentrating to dryness. The product after the reaction was designated as S11.

In order to verify the technical effect of the preparation method of the present invention, the following comparative examples were set.

Comparative example 1

Taking a 2L three-necked bottle, adding 200g of 4-fluorophenylethyl acetate, adding 280mL of 98% sulfuric acid solution, and cooling to 0-10 ℃. 83mL of 69% nitric acid was added dropwise over 30 minutes. The reaction was continued for 1 h. 500mL of water and 500mL of ethyl acetate were added to the reaction mixture, followed by extraction to separate an organic phase, washing with a saturated sodium bicarbonate solution, washing with water, and concentrating to dryness. The product after the reaction was designated as B1.

The amounts of the raw materials and some process parameters of the above examples 1 to 11 and comparative example 1 are shown in the following table 1.

TABLE 1 raw material quantities and part of the process parameters of examples 1 to 11 and comparative example 1

The products S1-S11 and B1 after the above examples and comparative examples had been reacted were content tested by HPLC and the results were recorded using area normalization.

Table 2 shows the conversion of the raw materials and the contents of the products in the above examples and comparative examples.

TABLE 2 feed conversion and product content for examples 1-11 and comparative example 1

As shown in fig. 1, the compound is a chemical structural general formula of a dihydronaphthyridine compound, and an important raw material for preparing the compound is 3-nitro-4-fluoroacetoacetate, so that the 3-nitro-4-fluoroacetoacetate is an important chemical intermediate compound; FIG. 2 shows the chemical structural formula of a specific compound, ethyl 3-nitro-4-fluorophenylacetate; FIG. 3 shows the reaction scheme for preparing 3-nitro-4-fluoroacetoacetate from 4-fluoroacetoacetate. FIG. 4 shows a reaction scheme for preparing ethyl 3-nitro-4-fluorophenylacetate by nitration of ethyl 4-fluorophenylacetate using a microreactor in the present invention.

As can be seen from table 2 above, when the preparation method S1-S11 of the present invention is used, the conversion rate of ethyl 4-fluorophenylacetate is high and the selectivity of 3-nitro-4-fluorophenylacetate and 2-nitro-4-fluorophenylacetate is also high, compared to the conventional nitration reaction B1.

The data in table 2 show that the conversion rate of ethyl 4-fluorophenylacetate in the reacted product S1 is the highest and the selectivity is the highest, which is the most preferred example. It can be seen that in example 1, the technical effects of high conversion rate of raw materials and strong space selectivity are obtained by defining the molar ratio of 4-fluorophenylethyl acetate to nitric acid, the amount of concentrated sulfuric acid, the respective flow rates and flow rate ratios of the mixed solution of 4-fluorophenylethyl acetate and concentrated sulfuric acid to nitric acid solution, controlling the reaction time, and the like, and by the synergistic effect of various parameters.

Compared with S1, the use amount of nitric acid is increased or reduced in the reaction process of S2-S5, so that the mixed solution of the ethyl 4-fluorophenylacetate and the concentrated sulfuric acid and the nitric acid can synchronously enter the microreactor for nitration reaction, the flow rate of the nitric acid is correspondingly increased or reduced, and the flow rate ratio of the mixed solution of the ethyl 4-fluorophenylacetate and the concentrated sulfuric acid to the nitric acid solution is changed; S6-S7 change the dosage of concentrated sulfuric acid, and correspondingly change the flow rate ratio of the mixed solution of 4-fluorophenylethyl acetate and concentrated sulfuric acid to the nitric acid solution; S8-S9 changed the reaction time. Namely, the preparation process parameters of S2-S9 are all not optimal, so that the conversion rate and the space selectivity of the raw materials are slightly poor, and the preparation method has certain synergistic effect among different process parameters, so that the collocation of the process parameters has great influence on the conversion rate and the space selectivity of the raw materials.

Examples 10 and 11 respectively show the preparation of methyl 3-nitro-4-fluoroacetate from methyl 4-fluoroacetate and isopropyl 3-nitro-4-fluoroacetate from isopropyl 4-fluoroacetate, and the results of table 2 show that the preparation methods of the present invention have high conversion rates of raw materials and high space selectivity, and thus the preparation methods of the present invention have a wide range of applications.

While the invention has been described with reference to a preferred embodiment, various modifications may be made thereto without departing from the scope of the invention. In particular, the technical features mentioned in the embodiments can be combined in any way as long as there is no conflict. It is intended that the invention not be limited to the particular embodiments disclosed, but that the invention will include all embodiments falling within the scope of the appended claims.

Claims

1. A preparation method of 3-nitro-4-fluoroacetoacetate is characterized by comprising the following steps: the preparation process is carried out in a microreactor, the microreactor comprises a precooling module and a mixing module, and the preparation process specifically comprises the following steps:

(1) preparing raw materials: preparing a mixed solution of 4-fluorophenylacetate and concentrated sulfuric acid and a nitric acid solution;

(4) quenching and post-treatment: after the reaction is finished, the reaction liquid enters a quenching tank for quenching, and is subjected to extraction, alkali washing and water washing;

the 3-nitro-4-fluoroacetophenone acetate is selected from one of 3-nitro-4-fluoroacetophenone methyl ester, 3-nitro-4-fluoroacetophenone ethyl ester, 3-nitro-4-fluoroacetophenone isopropyl ester and 3-nitro-4-fluoroacetophenone benzyl ester; correspondingly, the 4-fluorobenzene acetate is selected from one of 4-fluorobenzene methyl acetate, 4-fluorobenzene ethyl acetate, 4-fluorobenzene isopropyl acetate and 4-fluorobenzene benzyl acetate; the residence time of the mixing reaction in the step (3) is 20-80 s.

2. The method of claim 1, wherein: the molar ratio of the 4-fluorobenzene acetate to the nitric acid is 1: 1.0-2.0.

3. The method of claim 2, wherein: the molar ratio of the 4-fluorobenzene acetate to the nitric acid in the step (1) is 1: 1.1.

4. The method of claim 1, wherein: the preparation method of the mixed solution of the 4-fluorobenzene acetate and the concentrated sulfuric acid in the step (1) comprises the following steps: 4-fluorobenzeneacetate is dissolved in concentrated sulfuric acid, and the dosage of the concentrated sulfuric acid relative to the 4-fluorobenzeneacetate is 1.1-4.0 mL/g.

5. The method of claim 4, wherein: the dosage of the concentrated sulfuric acid is 1.4 mL/g.

6. The method of claim 1, wherein: the feeding flow rate of the mixed solution of the 4-fluorobenzene acetate and the concentrated sulfuric acid in the step (3) is 9-18 mL/min.

7. The method of claim 6, wherein: the feeding flow rate of the mixed solution of the 4-fluorobenzene acetate and the concentrated sulfuric acid in the step (3) is 15 mL/min.

8. The method of claim 7, wherein: and (3) the feeding flow rate ratio of the mixed solution of the 4-fluoroacetoacetate and the concentrated sulfuric acid in the step (3) to the nitric acid solution is 6-3: 1.