Synthesis method of 2-chloro-4-fluoro-5-nitrobenzoic acid

Abstract

The invention discloses a synthetic method of 2-chloro-4-fluoro-5-nitrobenzoic acid. The synthetic method comprises the following steps: preparing a mixed acid of nitric acid and sulfuric acid; the method comprises the following steps: mixing 2-chloro-4-fluorotrichlorotoluene and mixed acid to carry out nitration reaction, heating the reaction system without separation after the nitration reaction is finished to carry out hydrolysis reaction, and obtaining the 2-chloro-4-fluoro-5-nitrobenzoic acid by a one-pot method. The synthesis method is high in conversion rate, good in yield, low in cost, simple in process, convenient to operate, free of separation and purification of intermediate products in the midway and easy to realize industrial production.

Description

Technical Field

[0001] The invention relates to the technical field of pesticide and pharmaceutical intermediate preparation, and in particular to a method for synthesizing 2-chloro-4-fluoro-5-nitrobenzoic acid. Background Art

[0002] 2-Chloro-4-fluoro-5-nitrobenzoic acid, molecular formula C 7 H 3 ClFNO 4 , molecular weight 219.55, CAS number 114776-15-7, is an important organic synthesis intermediate and also an intermediate of the pesticide saflufenacil. The main synthesis methods are:

[0003] 1. Using 2-chloro-4-fluorobenzoic acid as raw material, it is prepared by mixed acid nitration. Documents EP0863142A1, WO0183459A2 and CN106905161A are all synthesized by this method. The applicant's experimental verification shows that the isomer content is generally 10%-20%, and multiple recrystallizations are required, resulting in large losses and a yield of about 40%; or heavy metals are used as catalysts, making wastewater treatment difficult.

[0004] 2. Using 2-chloro-4-fluorobenzotrichloride as raw material, and preparing it through mixed acid nitration and hydrolysis. The patent specification with publication number CN101142168A discloses a two-step technical scheme of using 2-chloro-4-fluorobenzotrichloride as raw material, reacting it with a mixture of sulfuric acid and nitric acid to obtain a 2-chloro-4-fluoro-5-nitrobenzotrichloride intermediate compound, and then hydrolyzing the intermediate to obtain 2-chloro-4-fluoro-5-nitrobenzoic acid. Although its specification Example 7 discloses a preparation method of 2-chloro-4-fluorobenzotrichloride by one-pot reaction to prepare 2-chloro-4-fluoro-5-nitrobenzoic acid, it is known that the yield of 2-chloro-4-fluoro-5-nitrobenzoic acid prepared by one-pot reaction disclosed in the patented technology is not as good as step-by-step operation. The reason is that the technical scheme of its one-pot method is to first lay a large amount of concentrated sulfuric acid as a base, and then add 2-chloro-4-fluorobenzotrichloride, and solid will be formed at this time, and accompanied by hydrogen chloride gas generation, which shows that the hydrolysis dechlorination process is already in progress at this time. Further, after forming solid to produce hydrogen chloride gas (hydrolysis dechlorination has occurred), a large amount of concentrated nitric acid is added for nitration, and the overall process is essentially hydrolysis first and then nitration. In addition, due to the limitation of specific operations such as the order of adding materials, the amount of sulfuric acid and nitric acid required for the preparation process of the one-pot method of the patented technology is obviously too large, and the cost is relatively high.

[0005] Therefore, it is necessary to find a green and environmentally friendly method for synthesizing 2-chloro-4-fluoro-5-nitrobenzoic acid with milder reaction conditions, simpler operation methods, higher product yield and purity, lower raw material cost. Summary of the invention

[0006] In view of the above technical problems and the shortcomings in the art, the present invention provides a method for synthesizing 2-chloro-4-fluoro-5-nitrobenzoic acid, which has high conversion rate, high yield and high purity of 2-chloro-4-fluoro-5-nitrobenzoic acid, low cost, simple process, convenient operation, no need to separate and purify intermediate products in the middle, and easy to realize industrial production.

[0007] The specific technical solutions are as follows:

[0008] A method for synthesizing 2-chloro-4-fluoro-5-nitrobenzoic acid comprises:

[0009] Prepare a mixture of nitric acid and sulfuric acid;

[0010] 2-Chloro-4-fluorotrichlorotoluene and the mixed acid are mixed to carry out nitration reaction. After the nitration reaction is completed, the reaction system is heated without separation to carry out hydrolysis reaction, so as to obtain 2-chloro-4-fluoro-5-nitrobenzoic acid in one pot.

[0011] The technical route for synthesizing 2-chloro-4-fluoro-5-nitrobenzoic acid of the present invention is to first provide a mixed acid of nitric acid and sulfuric acid, and then mix 2-chloro-4-fluorobenzotrichloride with the mixed acid to carry out a nitration reaction, wherein the mixing method is not limited, and the 2-chloro-4-fluorobenzotrichloride can be added to the mixed acid, or the mixed acid can be added to the 2-chloro-4-fluorobenzotrichloride. The adding method is also not particularly limited, but dropwise addition is a preferred scheme. After the nitration reaction is completed, the reaction system does not need to be separated, and the temperature can be directly raised to carry out a hydrolysis reaction, so that high-purity 2-chloro-4-fluoro-5-nitrobenzoic acid is obtained in a one-pot process with high yield.

[0012] In order to better implement the above process, the present invention can select any one or more combinations of the following technical solutions:

[0013] In the process of preparing the mixed acid of nitric acid and sulfuric acid of the present invention, in some embodiments, the nitric acid source may be nitric acid with a mass concentration of not less than 95%, and the sulfuric acid source may be sulfuric acid with a mass concentration of not less than 98%. For example, the nitric acid source may be fuming nitric acid with a concentration of not less than 95wt%, and the sulfuric acid source may be concentrated sulfuric acid with a concentration of not less than 98wt%. In some embodiments, the mass fraction of nitric acid in the mixed acid may be not less than 10%, for example, 10% to 40%, etc., and further may be 15% to 35%, etc., for example, 20%, 25%, 30%, etc.

[0014] The synthesis method of 2-chloro-4-fluoro-5-nitrobenzoic acid preferably mixes 2-chloro-4-fluorobenzotrichloride and the mixed acid according to the molar ratio of nitric acid and 2-chloro-4-fluorobenzotrichloride in the mixed acid (1.0-1.3):1.0 (for example, 1.05:1.0, 1.1:1.0, 1.15:1.0, 1.2:1.0, 1.25:1.0, etc.). Research has found that by adopting the synthesis method of the present invention, a mixed acid of nitric acid and sulfuric acid is prepared in advance, and 2-chloro-4-fluorobenzotrichloride and the mixed acid are mixed to carry out a nitration reaction, the following effects can be achieved: the amount of acid used is reduced, the cost of raw materials is reduced, and the yield and purity of 2-chloro-4-fluoro-5-nitrobenzoic acid are improved. The amount of acid used is reduced, and a suitable hydrolysis reaction environment is provided for the subsequent temperature-raising hydrolysis reaction, so that the entire synthesis process does not need to separate intermediate products, and the temperature can be directly raised for the hydrolysis reaction. It is unexpectedly found that the yield and purity of 2-chloro-4-fluoro-5-nitrobenzoic acid obtained in the one-pot synthesis process under such conditions and operations are higher.

[0015] The synthesis method of 2-chloro-4-fluoro-5-nitrobenzoic acid, in the mixed acid, the molar ratio of nitric acid to sulfuric acid is preferably (1.0-1.3):(1.5-3.0) (for example, 1.0:1.5, 1.05:1.5, 1.1:1.5, 1.15:1.5, 1.2:1.5, 1.25:1.5, 1.3:1.5, 1.0:2.0, 1.05:2.0, 1.1:2.0, 1.15:2.0, 1.2:2.0:, 1.25:2.0, 1.3:2.0, 1.0:2.5, 1.05:2.5 , 1.1:2.5, 1.15:2.5, 1.2:2.5, 1.25:2.5, 1.3:2.5, 1.0:3.0, 1.05:3.0, 1.1:3.0, 1.15:3.0, 1.2:3.0, 1.25:3.0, 1.3:3.0, etc.), further preferably 1:(1.15-3), which is beneficial to providing a suitable hydrolysis reaction environment for the subsequent hydrolysis reaction process, so as to better achieve the purpose of directly heating up the hydrolysis reaction without separation, and improve the yield and purity of 2-chloro-4-fluoro-5-nitrobenzoic acid.

[0016] In the synthesis method of 2-chloro-4-fluoro-5-nitrobenzoic acid, the temperature of the nitration reaction can be -10 to 30°C, for example, -5°C, 0°C, 5°C, 10°C, 15°C, 20°C, 25°C, etc.

[0017] The synthesis method of 2-chloro-4-fluoro-5-nitrobenzoic acid, the nitration reaction process preferably includes: keeping the temperature at -5 to 5°C for 5 to 7 hours, and then heating to 20 to 30°C until the nitration reaction is completed. Low temperature reaction at -5 to 5°C can complete the nitration reaction of most raw materials, and the remaining part reacts slowly. The present invention can complete the nitration reaction of the raw materials by appropriately raising the temperature, and is conducive to subsequent direct heating and hydrolysis without separation.

[0018] In the synthesis method of 2-chloro-4-fluoro-5-nitrobenzoic acid, the temperature of the hydrolysis reaction can be 50 to 100° C., preferably 60 to 80° C., more preferably 70 to 80° C., such as 75° C.

[0019] The synthesis method of 2-chloro-4-fluoro-5-nitrobenzoic acid may also include: reacting 2-chloro-4-fluorotoluene with chlorine gas under photocatalysis to generate 2-chloro-4-fluorotrichlorotoluene.

[0020] In the synthesis method of 2-chloro-4-fluoro-5-nitrobenzoic acid, the wavelength of the photocatalytic light can be 300 to 500 nm, preferably 400 to 410 nm, such as 405 nm.

[0021] In the synthesis method of 2-chloro-4-fluoro-5-nitrobenzoic acid, the temperature for the reaction of 2-chloro-4-fluorotoluene with chlorine under photocatalysis can be 50-150° C., preferably 60-100° C., more preferably 70-90° C., for example 85° C.

[0022] In the synthesis method of 2-chloro-4-fluoro-5-nitrobenzoic acid, the reaction time of 2-chloro-4-fluorotoluene and chlorine under photocatalysis is preferably 12 to 15 hours, such as 13 hours, to ensure that the intermediate state is completely converted into 2-chloro-4-fluorotrichlorotoluene.

[0023] In the synthesis method of 2-chloro-4-fluoro-5-nitrobenzoic acid, chlorine is preferably continuously introduced and always in excess during the reaction of 2-chloro-4-fluorotoluene with chlorine under photocatalysis.

[0024] In the synthesis method of 2-chloro-4-fluoro-5-nitrobenzoic acid, 2-chloro-4-fluorotoluene reacts with chlorine under photocatalysis to generate 2-chloro-4-fluorotrichlorotoluene, and then the reaction system removes excess chlorine without separation and is mixed with the mixed acid for nitration reaction.

[0025] The synthesis method of 2-chloro-4-fluoro-5-nitrobenzoic acid does not require the use of a solvent.

[0026] The synthesis method of 2-chloro-4-fluoro-5-nitrobenzoic acid may further include: adding the mixture obtained after the hydrolysis reaction into ice water, and filtering to obtain 2-chloro-4-fluoro-5-nitrobenzoic acid.

[0027] Compared with the prior art, the present invention has the following beneficial effects:

[0028] The present invention nitrates 2-chloro-4-fluorobenzotrichloride with mixed acid, and then directly heats and hydrolyzes to obtain high-yield, high-purity 2-chloro-4-fluoro-5-nitrobenzoic acid in one pot, with a yield exceeding 97% and a purity exceeding 98.5%. Among them, 2-chloro-4-fluorobenzotrichloride can be obtained by using 2-chloro-4-fluoro-toluene as a raw material, reacting with chlorine gas through photocatalysis in the absence of solvent. The synthesis method of the present invention has good connectivity with upstream and downstream reactions and treatment processes, and the use of solvents can be avoided as a whole.

[0029] The invention has high conversion rate, high yield and purity of 2-chloro-4-fluoro-5-nitrobenzoic acid, low cost, simple process, convenient operation and easy realization of industrial production.

[0030] The synthesis method of the present invention can reduce the amount of acid used, thereby improving the yield and purity of 2-chloro-4-fluoro-5-nitrobenzoic acid while reducing the cost of raw materials. The present invention has found that the reduction in the amount of acid used can also create conditions for subsequent process steps, for example, providing a suitable hydrolysis reaction environment for the subsequent temperature-raising hydrolysis reaction, so that the entire synthesis process does not require the separation of intermediate products, and the temperature can be directly raised to carry out the hydrolysis reaction. It is unexpectedly found that the yield and purity of 2-chloro-4-fluoro-5-nitrobenzoic acid obtained in the one-pot synthesis process under such conditions and operations are higher. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 It is the HPLC (high performance liquid chromatography) spectrum of the product in Example 1.

[0032] Figure 2 It is the HPLC spectrum of the product in Comparative Example 1.

[0033] Figure 3 It is the HPLC spectrum of the product in Comparative Example 2.

[0034] Figure 4 It is the HPLC spectrum of the product in Comparative Example 3.

[0035] Figure 5 It is the HPLC spectrum of the product in Comparative Example 4.

[0036] Figure 6 It is the HPLC spectrum of the product in Comparative Example 5. DETAILED DESCRIPTION

[0037] The present invention will be further described below in conjunction with the accompanying drawings and specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and are not used to limit the scope of the present invention.

[0038] The reagents and raw materials used in the present invention can be obtained through commercial channels or according to existing technologies.

[0039] Example 1

[0040] Prepare mixed acid: add 69.6 g (1.05 mol) of fuming nitric acid (95 wt%) into a reaction bottle, start stirring, cool to about 0°C, then dropwise add 200 g of concentrated sulfuric acid (98 wt%) (2.0 mol). Set aside.

[0041] 144.57 g (1.0 mol) of 2-chloro-4-fluorotoluene was added to the chlorination reaction bottle, stirring was started, the temperature was raised to 85°C under 405 nm photocatalysis, chlorine was continuously introduced, and the reaction was kept warm until the raw material and the intermediate state reaction reached the limit. The reaction lasted for about 13 hours to obtain 2-chloro-4-fluorotrichlorotoluene. Nitrogen was introduced to blow off the excess chlorine and proceed to the next step of reaction.

[0042] Add the prepared mixed acid to the chlorination reaction bottle at about 0℃. After 1 hour of addition, keep the temperature at -5~5℃ for 5 hours, then heat to 20~30℃ and keep the temperature until the raw materials react. Heat to 70~80℃ and keep the temperature for 2 hours until the nitrate reacts completely. Pour the reaction liquid into 1L ice water, stir for 1 hour, and filter to obtain 2-chloro-4-fluoro-5-nitrobenzoic acid. The reaction yield is 99%. The liquid phase is normalized to a purity of 99.1% (such as Figure 1 ).

[0043] Example 2

[0044] Prepare mixed acid: add 86.17 g (1.3 mol) of fuming nitric acid (95 wt%) into a reaction bottle, start stirring, cool to about 0°C, then dropwise add 200 g of concentrated sulfuric acid (98 wt%) (2.0 mol). Set aside.

[0045] 144.57 g (1.0 mol) of 2-chloro-4-fluorotoluene was added to the chlorination reaction bottle, stirring was started, the temperature was raised to 85°C under 405 nm photocatalysis, chlorine was continuously introduced, and the reaction was kept warm until the raw material and the intermediate state reaction reached the limit. The reaction lasted for about 13 hours to obtain 2-chloro-4-fluorotrichlorotoluene. Nitrogen was introduced to blow off the excess chlorine and proceed to the next step of reaction.

[0046] Add the prepared mixed acid to the chlorination reaction bottle at a temperature of about 0°C. After the addition is completed for 1 hour, keep the temperature at -5 to 5°C for 5 hours, then heat to 20 to 30°C and keep the temperature until the raw materials react completely. Heat to 70 to 80°C and keep the temperature for 2 hours until the nitrate reacts completely. Pour the reaction liquid into 1L ice water, stir for 1 hour, and filter to obtain 2-chloro-4-fluoro-5-nitrobenzoic acid. The reaction yield is 98%. The liquid phase normalization purity is 99.0%.

[0047] Example 3

[0048] Prepare mixed acid: add 69.6 g (1.05 mol) of fuming nitric acid (95 wt%) into a reaction bottle, start stirring, cool to about 0°C, then dropwise add 300 g of concentrated sulfuric acid (98 wt%) (3.0 mol). Set aside.

[0049] 144.57 g (1.0 mol) of 2-chloro-4-fluorotoluene was added to the chlorination reaction bottle, stirring was started, the temperature was raised to 85°C under 405 nm photocatalysis, chlorine was continuously introduced, and the reaction was kept warm until the raw material and the intermediate state reaction reached the limit. The reaction lasted for about 13 hours to obtain 2-chloro-4-fluorotrichlorotoluene. Nitrogen was introduced to blow off the excess chlorine and proceed to the next step of reaction.

[0050] Add the prepared mixed acid to the chlorination reaction bottle at a temperature of about 0°C. After the addition is completed for 1 hour, keep the temperature at -5 to 5°C for 5 hours, then heat to 20 to 30°C and keep the temperature until the raw materials react completely. Heat to 70 to 80°C and keep the temperature for 2 hours until the nitrate reacts completely. Pour the reaction liquid into 1L ice water, stir for 1 hour, and filter to obtain 2-chloro-4-fluoro-5-nitrobenzoic acid. The reaction yield is 99.1%. The liquid phase normalization purity is 98.8%.

[0051] Example 4

[0052] Prepare mixed acid: add 69.6 g (1.05 mol) of fuming nitric acid (95 wt%) into a reaction bottle, start stirring, cool to about 0°C, then dropwise add 150 g of concentrated sulfuric acid (98 wt%) (1.5 mol). Set aside.

[0053] 144.57 g (1.0 mol) of 2-chloro-4-fluorotoluene was added to the chlorination reaction bottle, stirring was started, the temperature was raised to 85°C under 405 nm photocatalysis, chlorine was continuously introduced, and the reaction was kept warm until the raw material and the intermediate state reaction reached the limit. The reaction lasted for about 13 hours to obtain 2-chloro-4-fluorotrichlorotoluene. Nitrogen was introduced to blow off the excess chlorine and proceed to the next step of reaction.

[0054] Add the prepared mixed acid to the chlorination reaction bottle at a temperature of about 0°C. After the addition is completed for 1 hour, keep the temperature at -5 to 5°C for 5 hours, then heat to 20 to 30°C and keep the temperature until the raw materials react completely. Heat to 70 to 80°C and keep the temperature for 2 hours until the nitrate reacts completely. Pour the reaction liquid into 1L ice water, stir for 1 hour, and filter to obtain 2-chloro-4-fluoro-5-nitrobenzoic acid. The reaction yield is 98.6%. The liquid phase normalization purity is 99.2%.

[0055] Example 5

[0056] Prepare mixed acid: add 86.17 g (1.3 mol) of fuming nitric acid (95 wt%) into a reaction bottle, start stirring, cool to about 0°C, then drop 150 g of concentrated sulfuric acid (98 wt%) (1.5 mol) and set aside.

[0057] 144.57 g (1.0 mol) of 2-chloro-4-fluorotoluene was added to the chlorination reaction bottle, stirring was started, the temperature was raised to 85°C under 405 nm photocatalysis, chlorine was continuously introduced, and the reaction was kept warm until the raw material and the intermediate state reaction reached the limit. The reaction lasted for about 13 hours to obtain 2-chloro-4-fluorotrichlorotoluene. Nitrogen was introduced to blow off the excess chlorine and proceed to the next step of reaction.

[0058] Add the prepared mixed acid to the chlorination reaction bottle at a temperature of about 0°C. After the addition is completed for 1 hour, keep the temperature at -5 to 5°C for 5 hours, then heat to 20 to 30°C and keep the temperature until the raw materials react completely. Heat to 70 to 80°C and keep the temperature for 2 hours until the nitrate reacts completely. Pour the reaction liquid into 1L ice water, stir for 1 hour, and filter to obtain 2-chloro-4-fluoro-5-nitrobenzoic acid. The reaction yield is 97.3%. The liquid phase normalization purity is 99.13%.

[0059] Example 6

[0060] Prepare mixed acid: add 86.17 g (1.3 mol) of fuming nitric acid (95 wt%) into a reaction bottle, start stirring, cool to about 0°C, then dropwise add 390 g of concentrated sulfuric acid (98 wt%) (3.9 mol). Set aside.

[0061] 144.57 g (1.0 mol) of 2-chloro-4-fluorotoluene was added to the chlorination reaction bottle, stirring was started, the temperature was raised to 85°C under 405 nm photocatalysis, chlorine was continuously introduced, and the reaction was kept warm until the raw material and the intermediate state reaction reached the limit. The reaction lasted for about 13 hours to obtain 2-chloro-4-fluorotrichlorotoluene. Nitrogen was introduced to blow off the excess chlorine and proceed to the next step of reaction.

[0062] Add the prepared mixed acid to the chlorination reaction bottle at a temperature of about 0°C. After the addition is completed for 1 hour, keep the temperature at -5 to 5°C for 5 hours, then heat to 20 to 30°C and keep the temperature until the raw materials react completely. Heat to 70 to 80°C and keep the temperature for 2 hours until the nitrate reacts completely. Pour the reaction liquid into 1L ice water, stir for 1 hour, and filter to obtain 2-chloro-4-fluoro-5-nitrobenzoic acid. The reaction yield is 97.1%. The liquid phase normalization purity is 99.0%.

[0063] Example 7

[0064] Prepare mixed acid: add 66.28g (1.0mol) of fuming nitric acid (95wt%) into a reaction bottle, start stirring, cool to about 0°C, then drop 115g of concentrated sulfuric acid (98wt%) (1.15mol) and set aside.

[0065] 144.57 g (1.0 mol) of 2-chloro-4-fluorotoluene was added to the chlorination reaction bottle, stirring was started, the temperature was raised to 85°C under 405 nm photocatalysis, chlorine was continuously introduced, and the reaction was kept warm until the raw material and the intermediate state reaction reached the limit. The reaction lasted for about 13 hours to obtain 2-chloro-4-fluorotrichlorotoluene. Nitrogen was introduced to blow off the excess chlorine and proceed to the next step of reaction.

[0066] Add the prepared mixed acid to the chlorination reaction bottle at a temperature of about 0°C. After the addition is completed for 1 hour, keep the temperature at -5 to 5°C for 5 hours, then heat to 20 to 30°C and keep the temperature until the raw materials react completely. Heat to 70 to 80°C and keep the temperature for 2 hours until the nitrate reacts completely. Pour the reaction liquid into 1L ice water, stir for 1 hour, and filter to obtain 2-chloro-4-fluoro-5-nitrobenzoic acid. The reaction yield is 97.0%. The liquid phase normalization purity is 98.9%.

[0067] Comparative Example 1 (using solvent in chlorination process)

[0068] Prepare mixed acid: add 69.6 g (1.05 mol) of fuming nitric acid (95 wt%) into a reaction bottle, start stirring, cool to about 0°C, then dropwise add 200 g of concentrated sulfuric acid (98 wt%) (2.0 mol). Set aside.

[0069] Add 144.57 g (1.0 mol) of 2-chloro-4-fluorotoluene into a chlorination reaction bottle, add 300 mL of chloroform, start stirring, and heat to 65°C under 405 nm photocatalysis (due to the presence of solvent chloroform, this is the temperature increase limit and the optimal condition), continue to introduce chlorine gas, and keep the temperature to react until the raw material and the intermediate state reach the limit. The reaction is about 20 hours to obtain 2-chloro-4-fluorotrichlorotoluene, and nitrogen gas is introduced to blow off excess chlorine for the next step of reaction.

[0070] Add the prepared mixed acid to the chlorination reaction bottle at about 0℃. After 1 hour of addition, keep the temperature at -5~5℃ for 5 hours, then raise the temperature to 20~30℃ and keep the temperature until the raw materials react completely. Raise the temperature to 60-70℃ (due to the presence of solvent chloroform, this is the temperature increase limit and the best condition) and keep the temperature for 5 hours until the nitrate reacts completely. Then pour the reaction liquid into 1L ice water, stir for 1 hour, and filter to obtain 2-chloro-4-fluoro-5-nitrobenzoic acid. The reaction yield is 69%. The liquid phase normalization purity is 92.8% (such as Figure 2 ).

[0071] Comparative Example 2 (using solvent in nitration process)

[0072] Prepare mixed acid: add 69.6 g (1.05 mol) of fuming nitric acid (95 wt%) into a reaction bottle, start stirring, cool to about 0°C, then dropwise add 200 g of concentrated sulfuric acid (98 wt%) (2.0 mol). Set aside.

[0073] 144.57 g (1.0 mol) of 2-chloro-4-fluorotoluene was added to the chlorination reaction bottle, stirring was started, the temperature was raised to 85°C under 405 nm photocatalysis, chlorine was continuously introduced, and the reaction was kept warm until the raw material and the intermediate state reaction reached the limit. The reaction lasted for about 13 hours to obtain 2-chloro-4-fluorotrichlorotoluene. Nitrogen was introduced to blow off the excess chlorine and proceed to the next step of reaction.

[0074] Add 200mL of dichloromethane to the chlorination reaction bottle and add the prepared mixed acid dropwise at a temperature of about 0℃. After the addition is completed for 1 hour, keep the temperature at -5 to 5℃ for 5 hours, then raise the temperature to 20 to 30℃ and keep the temperature until the raw materials react completely, then raise the temperature to 30-40℃ and keep the temperature for 5 hours (due to the presence of solvent dichloromethane, this is the best condition for temperature reaction) until the nitrate reacts completely, then pour the reaction liquid into 1L of ice water, stir for 1 hour, and filter to obtain 2-chloro-4-fluoro-5-nitrobenzoic acid. The reaction yield is 79%. The liquid phase is normalized to a purity of 87% (such as Figure 3 ).

[0075] Comparative Example 3 (increasing the amount of nitric acid)

[0076] Prepare mixed acid: add 89.6 g (1.35 mol) of fuming nitric acid (95 wt%) into a reaction bottle, start stirring, cool to about 0°C, then dropwise add 200 g of concentrated sulfuric acid (98 wt%) (2.0 mol). Set aside.

[0077] 144.57 g (1.0 mol) of 2-chloro-4-fluorotoluene was added to the chlorination reaction bottle, stirring was started, the temperature was raised to 85°C under 405 nm photocatalysis, chlorine was continuously introduced, and the reaction was kept warm until the raw material and the intermediate state reaction reached the limit. The reaction lasted for about 13 hours to obtain 2-chloro-4-fluorotrichlorotoluene. Nitrogen was introduced to blow off the excess chlorine and proceed to the next step of reaction.

[0078] Add the prepared mixed acid to the chlorination reaction bottle at about 0℃. After 1 hour of addition, keep the temperature at -5~5℃ for 5 hours, then heat to 20~30℃ and keep the temperature until the raw materials react. Heat to 70~80℃ and keep the temperature for 2 hours until the nitrate reacts completely. Pour the reaction liquid into 1L ice water, stir for 1 hour, and filter to obtain 2-chloro-4-fluoro-5-nitrobenzoic acid. The reaction yield is 85%. The liquid phase normalization purity is 95.3% (such as Figure 4 ).

[0079] Comparative Example 4 (increasing the amount of sulfuric acid)

[0080] Prepare mixed acid: add 69.6 g (1.05 mol) of fuming nitric acid (95 wt%) into a reaction bottle, start stirring, cool to about 0°C, then drop 400 g of concentrated sulfuric acid (98 wt%) (4.0 mol) and set aside.

[0081] 144.57 g (1.0 mol) of 2-chloro-4-fluorotoluene was added to the chlorination reaction bottle, stirring was started, the temperature was raised to 85°C under 405 nm photocatalysis, chlorine was continuously introduced, and the reaction was kept warm until the raw material and the intermediate state reaction reached the limit. The reaction lasted for about 13 hours to obtain 2-chloro-4-fluorotrichlorotoluene. Nitrogen was introduced to blow off the excess chlorine and proceed to the next step of reaction.

[0082] Add the prepared mixed acid to the chlorination reaction bottle at about 0℃. After 1 hour of addition, keep the temperature at -5~5℃ for 5 hours, then heat to 20~30℃ and keep the temperature until the raw materials react. Heat to 70~80℃ and keep the temperature for 2 hours until the nitrate reacts completely. Pour the reaction liquid into 1L ice water, stir for 1 hour, and filter to obtain 2-chloro-4-fluoro-5-nitrobenzoic acid. The reaction yield is 90%. The liquid phase is normalized to a purity of 96% (such as Figure 5 ).

[0083] Comparative Example 5 (Changing the Acid Addition Method)

[0084] 144.57 g (1.0 mol) of 2-chloro-4-fluorotoluene was added to the chlorination reaction bottle, stirring was started, the temperature was raised to 85°C under 405 nm photocatalysis, chlorine was continuously introduced, and the reaction was kept warm until the raw material and the intermediate state reaction reached the limit. The reaction lasted for about 13 hours to obtain 2-chloro-4-fluorotrichlorotoluene. Nitrogen was introduced to blow off the excess chlorine and proceed to the next step of reaction.

[0085] Into the chlorination reaction bottle, add 200g concentrated sulfuric acid (98wt%) (2.0mol) dropwise at about 0℃. After 1h of dropwise addition, add 69.6g (1.05mol) of fuming nitric acid (95wt%) dropwise. After 0.5h of dropwise addition, keep the temperature at -5~5℃ for 5h, then raise the temperature to 20~30℃ and keep the temperature until the raw materials react. Heat to 70~80℃ and keep the temperature for 2h until the nitrate reacts completely. Pour the reaction liquid into 1L ice water, stir for 1h, and filter to obtain 2-chloro-4-fluoro-5-nitrobenzoic acid. The reaction yield is 74%. The liquid phase is normalized to a purity of 76% (such as Figure 6 ).

[0086] In addition, it should be understood that after reading the above description of the present invention, those skilled in the art may make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A method for synthesizing 2-chloro-4-fluoro-5-nitrobenzoic acid, characterized in that: include: Prepare a mixture of nitric acid and sulfuric acid; 2-Chloro-4-fluorotrichlorotoluene and the mixed acid are mixed to carry out nitration reaction. After the nitration reaction is completed, the reaction system is heated without separation to carry out hydrolysis reaction, so as to obtain 2-chloro-4-fluoro-5-nitrobenzoic acid in one pot.

2. The synthesis method according to claim 1, characterized in that Mixing 2-chloro-4-fluorobenzotrichloride and the mixed acid according to the molar ratio of nitric acid to 2-chloro-4-fluorobenzotrichloride in the mixed acid (1.0-1.3):1.0; Furthermore, in the mixed acid, the molar ratio of nitric acid to sulfuric acid is (1.0-1.3):(1.5-3.0).

3. The synthesis method according to claim 1 or 2, characterized in that In the process of preparing the mixed acid of nitric acid and sulfuric acid, the source of nitric acid is nitric acid with a mass concentration of not less than 95%, and the source of sulfuric acid is sulfuric acid with a mass concentration of not less than 98%; and / or, In the mixed acid, the mass fraction of nitric acid is not less than 10%, further 10% to 40%, further 15% to 35%.

4. The synthesis method according to claim 1, characterized in that The temperature of the nitration reaction is -10 to 30°C; Furthermore, the nitration reaction process includes: keeping the temperature at -5 to 5°C for 5 to 7 hours, and then heating to 20 to 30°C until the nitration reaction is completed.

5. The synthesis method according to claim 1, characterized in that The temperature of the hydrolysis reaction is 50 to 100°C, preferably 60 to 80°C, and more preferably 70 to 80°C.

6. The synthesis method according to claim 1, characterized in that The synthesis method of 2-chloro-4-fluoro-5-nitrobenzoic acid also includes: 2-chloro-4-fluorotoluene reacts with chlorine gas under photocatalysis to generate 2-chloro-4-fluorotrichlorotoluene.

7. The synthesis method according to claim 6, characterized in that The wavelength of the photocatalytic light is 300 to 500 nm, preferably 400 to 410 nm.

8. The synthesis method according to claim 6, characterized in that The temperature for the photocatalytic reaction of 2-chloro-4-fluorotoluene with chlorine is 50 to 150° C., preferably 60 to 100° C., and more preferably 70 to 90° C.; and / or, The time for the reaction of 2-chloro-4-fluorotoluene with chlorine under photocatalysis is 12 to 15 hours; and / or, During the reaction of 2-chloro-4-fluorotoluene with chlorine under photocatalysis, chlorine is continuously introduced and always in excess.

9. The synthesis method according to claim 6, characterized in that: After 2-chloro-4-fluorotoluene reacts with chlorine under photocatalysis to generate 2-chloro-4-fluorotrichlorobenzol, the reaction system removes excess chlorine without separation and is mixed with the mixed acid to carry out nitration reaction.

10. The synthesis method according to claim 1, characterized in that The synthesis method of 2-chloro-4-fluoro-5-nitrobenzoic acid does not use a solvent.

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