Preparation method of aryl sulfonic acid compound

Abstract

The invention relates to the field of compound preparation, in particular to a novel preparation method of aryl sulfonic acid, which is characterized in that fluoropyridine containing electron-withdrawing substituents (substituents such as halogen, trifluoromethyl, nitryl, cyano and the like) is used as an initial raw material, and an aryl sulfonic acid compound is obtained through three-step reaction. According to the present invention, it is possible to provide a method for producing an aryl sulfonic acid-containing compound under relatively mild reaction conditions using an easily available compound.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical chemical synthesis, and in particular, relates to a novel preparation method of high-purity aryl sulfonic acid compounds. Background Art

[0002] Sulfonic acids and their salts are closely related to people's lives. They are widely used in the fields of medicine, printing and dyeing, pesticides, etc. They are important intermediates for the preparation of sulfonyl functional group-containing compounds such as sulfonamides and sulfonyl chlorides, and have high commercial value. In particular, aryl sulfonic acids and their derivatives, as active components for the preparation of intermediates or catalytic reactions, play a key role in the preparation of complex organic molecules, polymers and drug intermediates. However, there are some shortcomings in the preparation of sulfonic acid compounds at present: for example, the reaction requires a high pressure and low temperature environment, and the conditions are very harsh; the amount of volatile organic solvents used in the synthesis process is large; the reaction system is too complicated, the reaction time is long, and the reaction cost is high. Therefore, it is of great significance to develop a preparation route for aryl sulfonic acid compounds with mild reaction conditions, high efficiency and simplicity, and cheap and readily available raw materials.

[0003] In view of the wide application and market demand of aryl sulfonic acid compounds in many fields, the development of new aryl sulfonic acid compounds and their efficient and green preparation methods has become a hot topic in current research. In the prior art, although the preparation methods of aryl sulfonic acid compounds are diverse, there are still challenges in terms of yield, selectivity, environmental friendliness and cost control. Therefore, finding a better synthesis route, improving product quality, reducing production costs, and reducing environmental pollution are of great significance for promoting the industrial production and application of aryl sulfonic acid compounds. With the growing global demand for high-performance materials, green chemistry and sustainable development, aryl sulfonic acid compounds, as key chemical raw materials and intermediates, have huge market potential. Whether it is medical health, personal care, or electronic technology and new energy industries, aryl sulfonic acid compounds have an irreplaceable role. It is expected that in the next few years, its market demand will continue to expand, bringing broad development space for related technology research and development and industrial application. Prior art

[0004] Patent document 1: US5082944A Patent document 2: CN114853668A Summary of the invention Technical problem to be solved by the invention

[0005] Patent document US5082944A uses 3-chloropyridine N-oxide as the starting material, uses sodium bisulfite to oxidize in an autoclave at 145°C, and then uses Raney nickel to hydrogenate under high pressure and high temperature. This process uses high temperature and high pressure, and Raney nickel is flammable. The operation is very risky and cannot be achieved in industrial production.

[0006] Patent document CN114853668A uses 4-chloropyridine as the starting material and hydrogen peroxide as the oxidant to obtain 4-chloropyridine nitrogen oxide; then reacts with sodium sulfite under high pressure and 120°C to obtain 4-sodium sulfonate pyridine nitrogen oxide; finally, palladium carbon is used for hydrogenation to obtain 4-sulfonate pyridine. This process also uses high temperature and high pressure, hydrogen peroxide is explosive and extremely dangerous, and palladium carbon is expensive, which is not suitable for large-scale industrial production.

[0007] The present invention mainly combines the advantages and disadvantages of previous invention patents, and its purpose is to provide a new preparation method of aryl sulfonic acid compounds which is simple to operate, low in cost and capable of industrial production.

[0008] The invention uses simple and readily available fluoropyridine compounds containing electron-withdrawing substituents (halogen, trifluoromethyl, nitro, cyano and other substituents) as starting materials, and obtains high-purity aryl sulfonic acid compounds through three-step reactions. The preparation method is highly economical and simple to operate, and the obtained crude product can reach a purity of more than 98% through simple purification, is suitable for large-scale industrial production, and has high application potential. Technical means to solve technical problems

[0009] In order to achieve the above object, the present invention provides a method for preparing an aryl sulfonic acid compound by using a fluoropyridine compound containing an electron-withdrawing substituent (a halogen, trifluoromethyl, nitro, cyano or other substituent) as a starting material through a three-step reaction, comprising the following steps: (A) Substitution reaction: reacting a fluoropyridine compound containing an electron-withdrawing substituent with benzyl mercaptan in the presence of an inorganic base to obtain a benzylthiopyridine compound. (B) First oxidation reaction: After the benzylthiopyridine compound and NCS are mixed and stirred at room temperature under acidic conditions to complete the reaction, the pH of the system is adjusted to precipitate a solid to obtain a benzylsulfinylpyridine compound. (C) second oxidative hydrolysis reaction: NCS is added in batches and mixed with a benzylsulfinylpyridine compound, and then reacted under acidic conditions to obtain an arylsulfonic acid compound by crystallization; The chemical structural formula of the aryl sulfonic acid compound is as follows: Among them, R 1 is one selected from halogen, trifluoromethyl, nitro, and cyano, R 2 It is a sulfonic acid group.

[0010] In the above step (A), the substitution reaction is carried out at 20-90° C. for 2-10 hours, and the corresponding benzylthiopyridine compound is obtained through crystallization and filtration. In the above step (A), the inorganic base is sodium carbonate or potassium carbonate. In the above step (A), the benzylthiopyridine compound is obtained by crystallization by cooling at a temperature of 0 to 20°C.

[0011] In the above step (B), the benzylthiopyridine compound obtained in step (A) is stirred in an organic acid solvent in the presence of NCS at room temperature for 1 to 10 hours, and then the pH is adjusted, crystallized, and filtered to obtain the corresponding benzylsulfinylpyridine compound. In the above step (B), the amount of NCS used is 1.0 to 1.2 eq of the benzylthiopyridine compound. In the above step (B), the organic acid solvent is formic acid, acetic acid, oxalic acid or trifluoroacetic acid. In the above step (B), after the reaction is completed, the pH of the reaction system is adjusted to 4-6 for crystallization, and then 5V-15V purified water is added and stirred at room temperature for 1-6 hours to obtain a benzylsulfinylpyridine compound.

[0012] In step (C), the benzylsulfinylpyridine compound obtained in step (B) is reacted with NCS in an acid solution for 12 to 80 hours, and the arylsulfonic acid compound is obtained by adjusting the pH, extracting, backwashing impurities, and concentrating under reduced pressure and crystallizing. In the above step (C), the amount of NCS used is 2.0 to 2.2 eq of the benzylsulfinylpyridine compound, and more preferably 2.1 eq. In the above step (C), NCS is added in batches over a period of 2 to 10 hours. More preferably, NCS is added in four batches, with 1 eq added in the first batch, 0.5 eq added in the second batch, 0.5 eq added in the third batch, and 0.1 eq added in the fourth batch. In the above step (C), the acid solvent used in the reaction is formic acid, acetic acid, oxalic acid or trifluoroacetic acid. In the above step (C), the pH is adjusted to 1-2. In the above step (C), the crystallization solvent is acetone or acetonitrile. Effects of the Invention

[0013] According to the present invention, a novel preparation method of aryl sulfonic acid compounds is provided, which has the effects of taking advantage of advantages and avoiding disadvantages, easy availability of raw materials, mild reaction conditions, high chemical purity and wide application range.

[0014] Compared with the prior art, the present invention does not need to use expensive, dangerous and complex raw materials, and uses cheap and easily available electron-withdrawing substituted fluoropyridine as the initial raw material, eliminating the additional consumption required for necessary maintenance when using the aforementioned raw materials, and can greatly reduce costs; at the same time, the manufacturing method of the present invention has simple steps and mild conditions, clear reaction products, high atomic economy, and no column chromatography technology is required. Aryl sulfonic acid compounds can be obtained by simple crystallization, further saving time and cost. In addition, the present invention obtains high-purity aryl sulfonic acid compounds by setting the purification steps and conditions. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 is the mass spectrum (MS) of 5-chloropyridine-3-sulfonic acid prepared in Example 1 Figure 2 The HNMR spectrum of 5-chloropyridine-3-sulfonic acid prepared in Example 1 is Figure 3 is the mass spectrum (MS) of 5-nitropyridine-2-sulfonic acid prepared in Example 2 Figure 4 The HNMR spectrum of 5-nitropyridine-2-sulfonic acid prepared in Example 2 is Figure 5 is the mass spectrum (MS) of 5-bromopyridine-2-sulfonic acid prepared in Example 3 Figure 6 The HNMR spectrum of 5-bromopyridine-2-sulfonic acid prepared in Example 3 is DETAILED DESCRIPTION

[0016] The structural formula of the aryl sulfonic acid compound of the present invention is as follows: In the above structural formula, the substituent R on the pyridine ring 1 and R 2 The replacement position is not limited.

[0017] The synthetic route of the novel preparation method of the above-mentioned aryl sulfonic acid compounds of the present invention is as follows:

[0018] To realize the above synthesis route, the technical solution proposed by the present invention may specifically include the following steps: Step 1: A fluoropyridine compound containing an electron-withdrawing substituent (such as a halogen, trifluoromethyl, nitro, or cyano) undergoes a substitution reaction with benzyl mercaptan under alkaline conditions, and a high-purity benzylthiopyridine compound is obtained by cooling, adding seed crystals, and the like. The alkaline condition may use an inorganic base such as sodium carbonate or potassium carbonate; the cooling and crystallization temperature is 0 to 20°C.

[0019] Step 2: After the benzylthiopyridine compound is dissolved in an acid, an oxidation reaction is carried out in the presence of NCS (N-chlorosuccinimide) to generate a benzylsulfinylpyridine compound. The acid used in the reaction can be an acidic solvent such as formic acid, acetic acid (including glacial acetic acid), oxalic acid or trifluoroacetic acid, preferably glacial acetic acid. For the above oxidation reaction, metal catalysts are conventionally used in the art. In the present invention, NCS is used, which is very cheap compared to expensive metal catalysts, so it is a great advantage in terms of price. In addition, after using the metal catalyst, the metal needs to be removed in the post-processing, and reducing the metal content to the ppm level requires a lot of work, and even requires a specific metal adsorbent, which makes the process complicated and increases the cost.

[0020] Step 3: react the obtained high-purity benzylsulfinylpyridine with NCS in an acid solution for 12 to 60 hours, and obtain aryl sulfonic acid by adjusting pH, extraction, backwashing, and crystallization. The acid used in the reaction can be formic acid, acetic acid (including glacial acetic acid), oxalic acid or trifluoroacetic acid.

[0021] Furthermore, the technical solution proposed by the present invention preferably includes the following steps: 1) Fluoropyridine containing electron-withdrawing substituents (halogen, trifluoromethyl, nitro, cyano and other substituents) is reacted with benzyl mercaptan under alkaline conditions at 20-90°C for 2-10 hours, cooled, water and seed crystals are added for crystallization, and then filtered to obtain benzylthiopyridine. 2) The benzylthiopyridine obtained in 1) is dissolved in an acidic solvent, stirred for reaction at room temperature for 1 to 10 hours, and then the pH is adjusted, slurried with purified water, crystallized, and filtered to obtain benzylsulfinylpyridine. 3) reacting the benzylsulfinylpyridine obtained in 2) above with NCS in an acid solution for 12 to 80 hours, and obtaining an arylsulfonic acid through pH adjustment, extraction, backwashing and crystallization.

[0022] In the above-mentioned production method, in order to further obtain the effect of mild reaction conditions and improved yield, the following conditions are preferably adopted:

[0023] In the substitution reaction of the present invention, the reaction temperature and time can be appropriately set within the above range according to the target product. Preferably, fluoropyridine containing an electron-withdrawing substituent (a halogen, trifluoromethyl, nitro, cyano or other substituent) is reacted with benzyl mercaptan under alkaline conditions of potassium carbonate at 25°C to generate benzylthiopyridine. The reaction conditions are mild, the post-treatment is simple and convenient, and the yield can be further improved.

[0024] Preferably, benzylthiopyridine is dissolved in acetic acid, stirred and reacted with NCS at room temperature for 2h to 6h, and after the reaction, the pH of the system is adjusted to 4 to 6, preferably 3 to 4, to obtain benzylsulfinylpyridine. The reaction conditions are mild and can further improve the yield and purity. In the oxidation reaction of this step, the amount of NCS added can be appropriately controlled according to the final reaction product. In the present invention, it is preferably 1.0 to 1.2eq of the benzylthiopyridine compound. After adjusting the pH to crystallize it, preferably 5V to 15V volume of purified water is added relative to the mass of the reaction substrate in the reaction system at this time, and stirred at room temperature for 1 to 6h to obtain a benzylsulfinylpyridine compound. Usually 5 to 15ml of purified water is added relative to 1g of the reaction substrate.

[0025] Preferably, the obtained high-purity benzylsulfinylpyridine is added to an acid solution, and then 2.0 to 2.2 eq of NCS is added in batches for 2 to 10 hours, and then the reaction is continued for 12 to 60 hours, and the pH is adjusted to 1 to 2, and the impurities are extracted and backwashed, and the aryl sulfonic acid is obtained by crystallization using a solvent. The solvent for crystallization can be a conventional solvent in the art without affecting the reaction of the present invention, preferably acetone or acetonitrile.

[0026] As another aspect of the present invention, in the oxidation reaction of the present invention, since the oxidation reaction is difficult to carry out, it is extremely important for the selection of oxidant. Commonly used oxidants include nitrogen-containing compounds such as hydrogen peroxide, peracid, periodic acid and its salts, nitric acid, halogens and halides with electrophilicity, etc. However, meta-chloroperbenzoic acid (mCPBA) is expensive and is not suitable for large-scale industrial production; peracids such as peracetic acid and hydrogen peroxide are easy to make explosives, and are extremely dangerous and difficult to use in large quantities; periodic acid and its salts belong to strong oxidants, which are expensive and are not suitable for large-scale industrial production, and their wastewater is very likely to cause water and soil pollution, endangering the normal growth of water source ecosystems and crops; halogens such as chlorine and bromine are not easy to store, and are relatively toxic, and are not suitable for large-scale industrial production.

[0027] The present invention uses NCS as an oxidant, which is chemically stable, relatively safe, and has good tolerance to various functional groups in the substrate compared to other oxidants, and is in large quantities on the market at a low price. Therefore, it is more conducive to obtaining the target product with a higher yield gently. The NCS oxidation mechanism is speculated: first, the S atom of the intermediate benzyl sulfide attacks the N-Cl bond of NCS to produce sulfonium ions, and then the electrophilic sulfonium ions are attacked by the acetate nucleophilic attack in the reaction system to generate an intermediate (sulfur ylide) containing SO bond, and this intermediate further forms a sulfur oxygen four-membered ring intermediate state, and finally forms a benzylsulfinyl compound and a by-product acetaldehyde. The NCS used in the present invention can obtain higher selectivity than strong oxidants such as peroxyacids, and is then conducive to improving yield.

[0028] Further, in step three, it is necessary to add the oxidant in batches, which can ensure that the oxidation process is gentle enough, greatly improve the selectivity of the reaction, avoid excessive oxidation, and improve the yield of the reaction. The number of times the oxidant is added in batches can be determined according to the specific needs and conditions of the experiment, and there is no fixed number limit. In the present invention, the addition amount of the oxidant NCS is further preferably 2.1eq. From the perspective of improving yield and reducing by-products, it is preferred that the oxidant is added in four times, 1eq is added for the first time, 0.5eq is added for the second time, 0.5eq is added for the third time, and 0.1eq is added for the fourth time, wherein the time interval for each addition can be appropriately adjusted according to the progress of the reaction, preferably more than one hour.

[0029] Furthermore, when the final product is obtained in steps 2 and 3 of the present invention, the product can be maintained in an ionic state by adjusting the pH, which is further conducive to its precipitation with a higher yield and purity. Example

[0030] The embodiments of the present invention are described in detail below. It should be noted that the embodiments described below are exemplary and are only used to explain the present invention, and cannot be construed as limiting the present invention. In addition, unless otherwise explicitly stated, all reagents used in the following embodiments are commercially available, or can be synthesized according to this article or known methods, and the reaction conditions not listed are also easily available to those skilled in the art.

[0031] Example 1 Preparation of 5-chloropyridine-3-sulfonic acid

[0032] Preparation of 3-(Benzylthio)-5-chloropyridine In a dry reaction bottle, add 3-chloro-5-fluoropyridine (55.0g, 38mmol), anhydrous potassium carbonate (6.3g, 45.6mmol), 50ml DMF, benzyl mercaptan (4.7g, 38mmol), and heat and stir at 60°C for 5h under nitrogen protection. Monitor the disappearance of the raw materials by TLC (PE:EA=10:1) and stop heating. Cool the reaction system to room temperature, then add 150ml purified water, cool to 5-15°C, then add 10mg seed crystals, precipitate solids, control the temperature at 5-15°C and stir for 1h, filter, rinse the filter cake with 100ml purified water, and use an oil pump to vacuum dry at room temperature to obtain 8.5g of off-white solids, with a yield of 94.9% and a purity of 98.1%.

[0033] Preparation of 3-(Benzylsulfinyl)-5-chloropyridine To a dry and clean 100 ml reaction bottle, add 3-(benzylthio)-5-chloropyridine (7.9 g, 33.5 mmol), NCS (4.9 g, 36.9 mmol), 32 ml of glacial acetic acid, and 11 ml of purified water. After nitrogen protection, stir at room temperature for 2 h. Monitor the disappearance of the raw materials by TLC (PE: EA = 10: 1). Adjust the pH of the reaction system to 4 with saturated sodium bicarbonate aqueous solution to precipitate a white solid. Then add 80 ml of purified water, stir at room temperature for 1 h, filter, rinse the filter cake with 100 ml of purified water, and dry to obtain 7.6 g of a white solid with a yield of 90% and a purity of 99.2%.

[0034] Preparation of 5-chloropyridine-3-sulfonic acid In a dry reaction bottle, 3-(benzylsulfinyl)-5-chloropyridine (7.0 g, 27.8 mmol), 42 ml of acetic acid, and 7 ml of purified water were added. The mixture was stirred at room temperature under nitrogen protection. NCS (7.8 g, 58.4 mmol) was added in four batches within 6 h. After the addition, the mixture was stirred and reacted at room temperature for 24 h. Then 50 ml of 5% hydrochloric acid solution was added to the reaction system. The pH of the system was 1. 50 ml of dichloromethane was added, and the liquid was extracted. The aqueous phase was washed again with 50 ml of dichloromethane. The aqueous phase was retained and concentrated under reduced pressure at 60 ° C until a large amount of solid precipitated. 50 ml of acetone was added, and the mixture was stirred at room temperature for 1 h. The mixture was filtered, and the filter cake was rinsed with 10 ml of acetone. After drying, 4.0 g of white solid was obtained. The yield was 74.3% and the purity was 98.6%.

[0035] Example 2 Preparation of 5-nitropyridine-2-sulfonic acid

[0036] Preparation of 2-(Benzylthio)-5-nitropyridine In a dry reaction bottle, add 2-fluoro-5-nitropyridine (14.2g, 100mmol), anhydrous potassium carbonate (18.0g, 130mmol), 80ml DMF, benzyl mercaptan (13.0g, 105mmol), and stir at 20-30℃ for 2h under nitrogen protection. Monitor the disappearance of raw materials by TLC (PE:EA=19:1) and perform post-treatment. Cool the reaction system to 0-10℃, then add 250ml purified water, precipitate a large amount of solid, control the temperature at 0-20℃ and stir for 2h, filter, rinse the filter cake with 100ml purified water, and dry it at 45℃ to obtain 22.5g of light yellow solid, with a yield of 91.4% and a liquid phase purity of 98.6%.

[0037] Preparation of 2-(Benzylsulfinyl)-5-nitropyridine To a dry and clean reaction bottle, add 2-(benzylthio)-5-nitropyridine (20.0 g, 81.2 mmol), NCS (11.9 g, 89.3 mmol), 100 ml of glacial acetic acid, and 20 ml of purified water. After nitrogen protection, stir at room temperature for 2 h. Monitor the disappearance of the raw materials by TLC (PE:EA=19:1). Adjust the pH of the reaction system to 4 with saturated sodium bicarbonate aqueous solution to precipitate a white solid. Then add 800 ml of purified water, stir at room temperature for 6 h, filter, rinse the filter cake with 20 ml of purified water, and dry to obtain 20 g of white solid 2-(benzylsulfinyl)-5-nitropyridine with a yield of 93.9% and a purity of 99.2%.

[0038] Preparation of 5-nitropyridine-2-sulfonic acid In a dry reaction bottle, add 2-(benzylsulfinyl)-5-nitropyridine (15.0 g, 60.9 mmol), 90 ml of acetic acid, and 15 ml of purified water. Stir at room temperature under nitrogen protection. Add NCS (17.1 g, 127.9 mmol) in four batches within 10 h. Stir and react at room temperature for 20 hours. Add 100 ml of purified water and 70 ml of dichloromethane. Extract and separate the liquids. Wash the aqueous phase again with 50 ml of dichloromethane. Retain the aqueous phase. Concentrate the aqueous phase under reduced pressure at 60 ° C until a large amount of solid precipitates. Add 70 ml of acetone, stir at room temperature for 2 h, filter, rinse the filter cake with 10 ml of acetone, and obtain 8.5 g of white solid after drying. The yield is 68.4% and the purity is 98.8%.

[0039] Example 3 Preparation of 5-bromopyridine-2-sulfonic acid

[0040] Preparation of 2-(Benzylthio)-5-bromopyridine In a dry reaction bottle, add 5-bromo-2-fluoropyridine (80g, 454.6mmol), anhydrous potassium carbonate (81.7g, 591mmol), 400ml DMF, benzyl mercaptan (56.5g, 454.6mmol), and stir at 20-30℃ for 10h under nitrogen protection. Monitor the disappearance of raw materials by TLC (PE:EA=50:1) and perform post-treatment. Cool the reaction system to 0-10℃, then add 1500ml purified water, precipitate a large amount of solid, control the temperature at 0-20℃ and stir for 2h, filter, rinse the filter cake with 100ml purified water, then rinse with 100ml n-hexane (0℃), and dry with air at 30℃ to obtain 120g of off-white solid, with a yield of 94.2% and a liquid phase purity of 99.2%.

[0041] Preparation of 2-Benzylsulfinyl-5-bromopyridine To a dry and clean reaction bottle, add 2-(benzylthio)-5-bromopyridine (56.8 g, 202.6 mmol), NCS (29.8 g, 222.9 mmol), 360 ml of glacial acetic acid, and 60 ml of purified water. After nitrogen protection, stir at room temperature for 10 h. Monitor the disappearance of the raw materials by TLC (PE:EA=19:1). Adjust the pH of the reaction system to 4 with saturated sodium bicarbonate aqueous solution to precipitate a white solid. Then add 600 ml of purified water, stir at room temperature for 2 h, filter, rinse the filter cake with 100 ml of purified water, and dry to obtain 55 g of white solid 2-(benzylsulfinyl)-5-bromopyridine with a yield of 91.6% and a purity of 99.3%.

[0042] Preparation of 5-bromopyridine-2-sulfonic acid In a dry reaction bottle, add 2-(benzylsulfinyl)-5-bromopyridine (24g, 81.0mmol), 100ml acetic acid, 15ml purified water, stir at room temperature, protect with nitrogen, add NCS (22.7g, 170.1mmol) in four batches within 8h, stir and react at room temperature for 24h, then add 50ml 5% hydrochloric acid solution to the reaction system, the pH of the system is 1, add 100ml dichloromethane, extract and separate, wash the aqueous phase again with 100ml dichloromethane, retain the aqueous phase, concentrate the aqueous phase under reduced pressure at 60°C until a large amount of solid precipitates, add 100ml acetonitrile, stir at room temperature for 1h, filter, rinse the filter cake with 10ml acetonitrile, and obtain 13g white solid after drying, with a yield of 67.4% and a purity of 98.9%.

[0043] Example 4 In Example 1, except for changing the amount of NCS in the second step to 4.9 g (33.5 mmol), that is, the amount relative to 3-(benzylthio)-5-chloropyridine is 1.0 eq, the rest of the operations are the same as in Example 1 to obtain 7.1 g of 3-(benzylsulfinyl)-5-chloropyridine with a yield of 89.9% and a purity of 99.1%. The same operation as in Example 1 was carried out except that the amount of NCS in the third step was changed to 7.4 g (55.6 mmol), i.e., 2.0 eq relative to 3-(benzylsulfinyl)-5-chloropyridine, to obtain 3.6 g of the final product with a yield of 65.0% and a purity of 98.4%.

[0044] Example 5 In Example 1, except that the amount of NCS in the second step was changed to 5.4 g (40.2 mmol), that is, the amount relative to 3-(benzylthio)-5-chloropyridine was 1.2 eq, the rest was carried out in the same manner as in Example 1 to obtain 7.0 g of 3-(benzylsulfinyl)-5-chloropyridine with a yield of 88.6% and a purity of 99.3%. The same operation as in Example 1 was carried out except that the amount of NCS in the third step was changed to 8.2 g (61.2 mmol), i.e., 2.2 eq relative to 3-(benzylsulfinyl)-5-chloropyridine, to obtain 3.8 g of the final product with a yield of 70.6% and a purity of 98.5%.

[0045] Comparative Example 1 In Example 1, as a purification step for the final product, the pH of the system was adjusted to precipitate it, extracted three times with 300 mL of ethyl acetate, and then the organic phase was washed with saturated brine until it was pure, then dried over anhydrous sodium sulfate, and concentrated to obtain the product with a yield of 100% and a purity of 85%.

[0046] Comparative Example 2 In Example 1, except that the amount of NCS in the second step was changed to 0.9 eq relative to 3-(benzylthio)-5-chloropyridine, the other operations were similar to Example 1 to obtain 3-(benzylsulfinyl)-5-chloropyridine with a yield of 80% and a purity of 96%. The final product was obtained in the same manner as in Example 1 except that the amount of NCS used in the third step was changed to 1.9 eq relative to 3-(benzylsulfinyl)-5-chloropyridine. The yield was 45% and the purity was 95%.

[0045] Comparative Example 3 In Example 1, except that the amount of NCS in the second step was changed to 1.3 eq relative to 3-(benzylthio)-5-chloropyridine, the other operations were similar to Example 1 to obtain 3-(benzylsulfinyl)-5-chloropyridine with a yield of 85% and a purity of 98%. The final product was obtained in the same manner as in Example 1 except that the amount of NCS used in the third step was changed to 2.3 eq relative to 3-(benzylsulfinyl)-5-chloropyridine. The yield was 60% and the purity was 95%.

[0046] Comparative Example 4 In Example 1, except that all NCS was added at once in the third step without dividing into batches, the rest was carried out in the same manner as in Example 1, but the target compound was not obtained.

[0047] In summary, the above description of the specific embodiments of the present invention does not limit the present invention. Those skilled in the art may make changes or modifications based on the present invention. However, as long as they do not deviate from the spirit of the present invention, they should all fall within the scope of the claims attached to the present invention.

Claims

1. A method for preparing an aryl sulfonic acid compound, characterized in that: Using a fluoropyridine compound containing an electron-withdrawing substituent as a starting material, an aryl sulfonic acid compound is obtained through a three-step reaction; The steps include: (A) Substitution reaction: reacting a fluoropyridine compound containing an electron-withdrawing substituent with benzyl mercaptan in the presence of an inorganic base to obtain a benzylthiopyridine compound. (B) First oxidation reaction: After the above-mentioned benzylthiopyridine compound is mixed with NCS and reacted at room temperature under acidic conditions, the pH of the system is adjusted to precipitate the benzylsulfinylpyridine compound, (C) second oxidative hydrolysis reaction: NCS is added in batches and mixed with a benzylsulfinylpyridine compound, and then reacted under acidic conditions to obtain an arylsulfonic acid compound by crystallization; The chemical structural formula of the aryl sulfonic acid compound is as follows: Wherein, R1 is one selected from halogen, trifluoromethyl, nitro, and cyano, and R2 is a sulfonic acid group.

2. The method for preparing an aryl sulfonic acid compound according to claim 1, characterized in that: In step (A), the substitution reaction is carried out at 20-90° C. for 2-10 hours, and the corresponding benzylthiopyridine compound is obtained through crystallization and filtration.

3. The method for preparing an aryl sulfonic acid compound according to claim 1 or 2, characterized in that: In step (A), the inorganic base is sodium carbonate or potassium carbonate.

4. The method for preparing an aryl sulfonic acid compound according to claim 1 or 2, characterized in that: In step (A), the benzylthiopyridine compound is obtained by crystallization by cooling at a temperature of 0 to 20°C.

5. The method for preparing an aryl sulfonic acid compound according to claim 1 or 2, characterized in that: In the step (B), the amount of NCS used is 1.0 to 1.2 eq of the benzylthiopyridine compound.

6. The method for preparing an aryl sulfonic acid compound according to claim 1 or 2, characterized in that: In step (B), the benzylthiopyridine compound obtained in step (A) is stirred in an organic acid solvent in the presence of NCS at room temperature for 1 to 10 hours, and then the pH is adjusted, crystallized, and filtered to obtain the corresponding benzylsulfinylpyridine compound.

7. The method for preparing an aryl sulfonic acid compound according to claim 6, characterized in that: In step (B), the organic acid solvent is formic acid, acetic acid, oxalic acid or trifluoroacetic acid.

8. The method for preparing an aryl sulfonic acid compound according to claim 6, characterized in that: In step (B), after the reaction is completed, the pH of the reaction system is adjusted to 4-6 for crystallization, and then 5V-15V purified water is added and stirred at room temperature for 1-6 hours to obtain a benzylsulfinylpyridine compound.

9. The method for preparing an aryl sulfonic acid compound according to claim 1 or 2, characterized in that: In the step (C), the amount of NCS used is 2.0 to 2.2 eq of the benzylsulfinylpyridine compound.

10. The method for preparing an aryl sulfonic acid compound according to claim 9, characterized in that: In the step (C), NCS is added in batches over a period of 2 to 10 hours.

11. The method for preparing an aryl sulfonic acid compound according to claim 10, characterized in that: In the step (C), the amount of NCS used is 2.1 eq of the benzylsulfinylpyridine compound.

12. The method for preparing an aryl sulfonic acid compound according to claim 11, characterized in that: NCS was added in four portions, 1 eq in the first portion, 0.5 eq in the second portion, 0.5 eq in the third portion, and 0.1 eq in the fourth portion.

13. The method for preparing an aryl sulfonic acid compound according to claim 1 or 2, characterized in that: In step (C), the benzylsulfinylpyridine compound obtained in step (B) is reacted with NCS in an acid solution for 12 to 80 hours, and the arylsulfonic acid compound is obtained by adjusting the pH to 1 to 2, extracting, backwashing impurities, and concentrating under reduced pressure and crystallizing.

14. The method for preparing an aryl sulfonic acid compound according to claim 13, characterized in that: In the step (C), the acid solvent used in the reaction is formic acid, acetic acid, oxalic acid or trifluoroacetic acid. In the step (C), the crystallization solvent is acetone or acetonitrile.

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