A method for preparing an arylsulfonic acid compound

Abstract

The present application relates to the field of compound preparation, in particular to a novel preparation method of aryl sulfonic acid, which uses fluoropyridine containing electron-withdrawing substituents (halogen, trifluoromethyl, nitro, cyano and the like) as starting material, and obtains aryl sulfonic acid compound through three-step reaction. According to the present application, a preparation method for manufacturing aryl sulfonic acid compound using easily obtained compound under relatively mild reaction condition can be provided.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of pharmaceutical chemical synthesis, and specifically relates to a novel preparation method of a high-purity aryl sulfonic acid compound. BACKGROUND

[0002] Sulfonic acids and their salts are closely related to people's daily life and have wide applications in the fields of medicine, printing and dyeing, pesticides, etc. They are important intermediates for preparing sulfonamide, sulfonyl chloride and other compounds containing sulfonyl functional groups, and have high commercial value. Especially, aryl sulfonic acids and their derivatives, as active components for preparing intermediates or catalyzing reactions, play a key role in the preparation of complex organic molecules, polymers and pharmaceutical intermediates. However, the current preparation of sulfonic acid compounds has some shortcomings: the reaction needs high pressure and low temperature environment, the conditions are very harsh; the use amount of volatile organic solvents in the synthesis process is large; the reaction system is too complex, the reaction time is long, and the reaction cost is high. Therefore, it is of great significance to develop a preparation route of aryl sulfonic acid compounds with mild reaction conditions, high efficiency, simplicity and cheap raw materials.

[0003] In view of the wide application and market demand of aryl sulfonic acid compounds in many fields, developing new aryl sulfonic acid compounds and their efficient and green preparation methods has become a research hotspot. In the prior art, although there are various preparation methods of aryl sulfonic acid compounds, there are still challenges in yield, selectivity, environmental friendliness and cost control. Therefore, it is of great significance to find a better synthesis route, improve product quality, reduce production cost, and reduce environmental pollution, for promoting the industrialization production and application of aryl sulfonic acid compounds. With the increasing demand for high-performance materials, green chemistry and sustainable development worldwide, aryl sulfonic acid compounds, as key chemical raw materials and intermediates, have huge market potential. Whether in the fields of medicine and health, personal care, electronic technology or new energy industry, aryl sulfonic acid compounds have an irreplaceable role, and it is expected that their market demand will continue to expand in the next few years, bringing broad development space for related technology research and industrialization application.

[0004] PRIOR ART

[0005] Patent document 1: US5082944A

[0006] Patent document 2: CN114853668A SUMMARY

[0007] TECHNICAL PROBLEMS TO BE SOLVED BY THE INVENTION

[0008] Patent document US5082944A uses 3-chloropyridine N-oxide as a starting material, sodium bisulfite is used for oxidation at 145℃ in an autoclave, and then Raney nickel is used for hydrogenation at high pressure and high temperature. This process uses high temperature and high pressure, Raney nickel is flammable, and there is a very high risk in operation, which cannot realize industrial production.

[0009]

[0010] In patent document CN114853668A, 4-chloropyridine is used as a starting material, and hydrogen peroxide is used as an oxidant to obtain 4-chloropyridine N-oxide; then sodium sulfite is reacted at high pressure and 120℃ to obtain 4-sodium sulfonate pyridine N-oxide; finally, palladium-carbon hydrogenation is used to obtain 4-sulfonic acid pyridine. This process also uses high temperature and high pressure, hydrogen peroxide is explosive, and the risk is extremely high, and palladium-carbon is expensive, which is not suitable for large-scale industrial production.

[0011]

[0012] The present application mainly combines the advantages and disadvantages of previous invention patents, and aims to provide a novel preparation method of aryl sulfonic acid compounds which is simple to operate, low in cost and capable of industrial production.

[0013] The present application uses simple and easily available fluoropyridine compounds containing electron-withdrawing substituents (halogen, trifluoromethyl, nitro, cyano and the like) as starting materials, and obtains aryl sulfonic acid compounds with high purity through three-step reactions. The preparation method is high in economy and simple in operation, and the crude product obtained can reach a purity of more than 98% after simple purification, which is suitable for large-scale industrial production and has high application potential.

[0014] Technical means for solving the technical problem

[0015] In order to achieve the above-mentioned purpose, the present application provides a preparation method of aryl sulfonic acid compounds using fluoropyridine compounds containing electron-withdrawing substituents (halogen, trifluoromethyl, nitro, cyano and the like) as starting materials, which comprises the following steps:

[0016] (A) Substitution reaction: reacting fluoropyridine compounds containing electron-withdrawing substituents with benzyl mercaptan in the presence of inorganic base to obtain benzylthio pyridine compounds,

[0017] (B) First oxidation reaction: mixing the above-mentioned benzylthio pyridine compounds with NCS, stirring at room temperature under acidic conditions to complete the reaction, adjusting the pH of the system to precipitate solid to obtain benzylsulfinyl pyridine compounds,

[0018] (C) second oxidative hydrolysis reaction: NCS is added in batches and mixed with the benzylsulfinyl pyridine compound, and then the reaction is carried out under acidic conditions to obtain an aryl sulfonic acid compound by crystallization;

[0019] The chemical structure of the aryl sulfonic acid compound is as follows:

[0020]

[0021] wherein R1 is one selected from halogen, trifluoromethyl, nitro, cyano, and R2 is a sulfonic acid group.

[0022] In the above step (A), the substitution reaction is carried out at 20-90°C for 2-10 h, and the corresponding benzylsulfanyl pyridine compound is obtained by crystallization and filtration.

[0023] In the above step (A), the inorganic base is sodium carbonate or potassium carbonate.

[0024] In the above step (A), the benzylsulfanyl pyridine compound is obtained by crystallization by cooling at a temperature of 0-20°C.

[0025] In the above step (B), the benzylsulfanyl pyridine compound obtained in step (A) is stirred in an organic acid solvent in the presence of NCS at room temperature for 1-10 h, and then the corresponding benzylsulfinyl pyridine compound is obtained by adjusting the pH, crystallization, and filtration.

[0026] In the above step (B), the amount of NCS used is 1.0-1.2 eq of the benzylsulfanyl pyridine compound.

[0027] In the above step (B), the organic acid solvent is formic acid, acetic acid, oxalic acid, or trifluoroacetic acid.

[0028] In the above step (B), after the reaction is completed, the reaction system is adjusted to a pH of 4-6 for crystallization, and then 5V-15V of purified water is added for stirring at room temperature for 1-6 h to obtain the benzylsulfinyl pyridine compound.

[0029] In step (C), the benzylsulfinyl pyridine compound obtained in step (B) is reacted with NCS in an acid solution for 12-80 h, and then the aryl sulfonic acid compound is obtained by adjusting the pH, extraction, impurity removal, concentration under reduced pressure, and crystallization.

[0030] In the above step (C), the amount of NCS used is 2.0-2.2 eq of the benzylsulfinyl pyridine compound, and further preferably 2.1 eq.

[0031] In the above step (C), the NCS is added in batches with an addition time of 2 to 10 hours, and it is further preferred that the NCS is added in four times, 1 eq in the first time, 0.5 eq in the second time, 0.5 eq in the third time, and 0.1 eq in the fourth time.

[0032] In the above step (C), the acid solvent used in the reaction is formic acid, acetic acid, oxalic acid, or trifluoroacetic acid.

[0033] In the above step (C), the pH is adjusted to 1 to 2.

[0034] In the above step (C), the crystallization solvent is acetone or acetonitrile.

[0035] Inventive Effects

[0036] According to the present application, a novel preparation method of aryl sulfonic acid compounds is provided, which has the effects of making the best of advantages and avoiding disadvantages, raw materials being easy to obtain, mild reaction conditions, high chemical purity, and wide application range.

[0037] Compared with the prior art, the present application does not need to use expensive, dangerous, and complex-structured raw materials, but uses electron-withdrawing substituted fluoropyridines which are inexpensive and easy to obtain, thereby saving additional consumption required for necessary maintenance when using the aforementioned raw materials, and greatly reducing the cost. Meanwhile, the manufacturing method of the present application has simple step operation, mild conditions, clear reaction products, and high atom economy, does not need to use column chromatography technology, and can obtain aryl sulfonic acid compounds through simple crystallization, thereby further saving time and cost. In addition, the present application obtains aryl sulfonic acid compounds with high purity by setting the purification step and conditions. BRIEF DESCRIPTION OF DRAWINGS

[0038] Figure 1 is a mass spectrum (MS) of 5-chloropyridine-3-sulfonic acid prepared in Example 1

[0039] Figure 2 is a proton nuclear magnetic resonance spectrum (HNMR) of 5-chloropyridine-3-sulfonic acid prepared in Example 1

[0040] Figure 3 is a mass spectrum (MS) of 5-nitropyridine-2-sulfonic acid prepared in Example 2

[0041] Figure 4 is a proton nuclear magnetic resonance spectrum (HNMR) of 5-nitropyridine-2-sulfonic acid prepared in Example 2

[0042] Figure 5 is a mass spectrum (MS) of 5-bromopyridine-2-sulfonic acid prepared in Example 3

[0043] Figure 6HNMR of 5-bromopyridine-2-sulfonic acid prepared in Example 3 DETAILED DESCRIPTION

[0044] The aryl sulfonic acid compound of the present application has the following structural formula:

[0045]

[0046] In the above structural formula, the substitution positions of the substituents R1and R2on the pyridine ring are not limited.

[0047] The synthetic route of the novel preparation method of the above aryl sulfonic acid compound of the present application is as follows:

[0048]

[0049] To achieve the above synthetic route, the technical solution proposed by the present application can specifically include the following steps:

[0050] Step one: under alkaline conditions, the fluoropyridine compound containing an electron-withdrawing substituent (halogen, trifluoromethyl, nitro, cyano, etc.) is subjected to a substitution reaction with benzyl mercaptan to generate a high-purity benzylthio pyridine compound through cooling, seeding, etc. The alkaline conditions can use sodium carbonate, potassium carbonate, etc. The cooling and crystallization temperature is 0-20°C.

[0051] Step two: after the benzylthiopyridine compound is dissolved with an acid, an oxidation reaction occurs in the presence of NCS (N-chlorosuccinimide) to generate a benzylsulfinyl pyridine compound. The acid used in the reaction can use formic acid, acetic acid (including glacial acetic acid), oxalic acid or trifluoroacetic acid, etc. The acid solvent, preferably glacial acetic acid.

[0052] For the above oxidation reaction, metal catalysts are commonly used in the art. In the present application, NCS is used, which is much cheaper than expensive metal catalysts, so it is a great advantage in price. In addition, after using a metal catalyst, a large amount of work is needed to remove the metal in the post-treatment to reduce the metal content to the ppm level, and even a special metal adsorbent is needed, which makes the process cumbersome and increases the cost.

[0053] Step three: the obtained high-purity benzylsulfinyl pyridine is reacted with NCS in an acid solution for 12-60 h, and the aryl sulfonic acid is obtained by adjusting the 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.

[0054] Further, the technical solution proposed by the present application preferably includes the following steps:

[0055] 1) Fluoropyridine containing electron-withdrawing substituents (halogen, trifluoromethyl, nitro, cyano, etc. substituents) is reacted with benzyl mercaptan in basic conditions at 20-90°C for 2-10 h, after cooling, water and seed crystal are added to induce crystallization, and then suction filtration is performed to obtain benzylsulfanylpyridine.

[0056] 2) The benzylsulfanylpyridine obtained in 1) above is dissolved in an acidic solvent, and after stirring at room temperature for 1-10 h, the pH is adjusted, and the product is washed, crystallized, and suction filtered to obtain benzylsulfinylpyridine.

[0057] 3) The benzylsulfinylpyridine obtained in 2) above is reacted with NCS in an acid solution for 12-80 h, and after adjusting the pH, extraction, backwashing, and crystallization, an aryl sulfonic acid is obtained.

[0058] In the above manufacturing method, in order to further obtain a mild reaction condition and improve the yield, the following conditions are preferably used:

[0059] In the above substitution reaction of the present application, the reaction temperature and time can be appropriately set within the above range according to the target product. Preferably, fluoropyridine containing electron-withdrawing substituents (halogen, trifluoromethyl, nitro, cyano, etc. substituents) is reacted with benzyl mercaptan in a potassium carbonate basic condition at 25°C to produce benzylsulfanylpyridine, which is a mild reaction condition, simple and convenient for post-treatment, and can further improve the yield.

[0060] Preferably, the benzylsulfanylpyridine is dissolved in acetic acid, and stirred with NCS at room temperature for 2-6 h, and after the reaction is completed, the pH of the system is adjusted to 4-6, preferably 3-4, to obtain benzylsulfinylpyridine. This reaction condition is 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, and in the present application, 1.0-1.2 eq of benzylsulfanylpyridine compound is preferred. After adjusting the pH to induce crystallization, 5V-15V of purified water is added relative to the mass of the reaction substrate in the reaction system at this time, and stirring is performed at room temperature for 1-6 h to obtain the benzylsulfinylpyridine compound. Generally, 5-15 ml of purified water is added relative to 1 g of reaction substrate.

[0061] Preferably, the obtained high-purity benzylsulfinylpyridine is added to an acid solution, and then 2.0-2.2 eq of NCS is added in batches, the addition time is 2-10 h, and then the reaction is continued for 12-60 h, after adjusting the pH to 1-2, extraction, backwashing of impurities, and crystallization using a solvent, an aryl sulfonic acid is obtained. The solvent used for crystallization can be a conventional solvent in the art without affecting the reaction of the present application, and acetone or acetonitrile is preferred.

[0062] As another aspect of the present application, in the oxidation reaction of the present application, since the oxidation reaction is difficult to proceed, the selection of the oxidizing agent is extremely important. Commonly used oxidizing agents include hydrogen peroxide, peroxy acid, periodic acid and its salts, nitrogen-containing compounds such as nitric acid, halogens, and electrophilic halides. However, mCPBA is expensive and not suitable for large-scale industrial production; peroxy acids such as peroxy acetic acid and hydrogen peroxide are extremely dangerous and difficult to use in large quantities because they are explosive; periodic acid and its salts are strong oxidizing agents, expensive, and not suitable for large-scale industrial production, and their wastewater can easily pollute water bodies and soil, harming water ecosystems and the normal growth of crops; halogens such as chlorine and bromine are not easy to store and are highly toxic, making them unsuitable for large-scale industrial production.

[0063] In the present application, NCS is used as an oxidizing agent. Compared with other oxidizing agents, NCS is chemically stable, relatively safe, has good tolerance to various functional groups in the substrate, and is widely available on the market at a low price. Therefore, it is more conducive to obtaining the target product in a mild manner with a high yield. The oxidation mechanism of NCS is speculated as follows: first, the S atom of the intermediate benzyl sulfide attacks the N-Cl bond of NCS to generate a sulfonium ion, then the electrophilic sulfonium ion is attacked by the acetate in the reaction system to generate an intermediate containing an S-O bond (sulfur ylide), the intermediate further forms a sulfur-oxygen tetra-ring intermediate state, and finally the benzyl sulfinyl compound and the byproduct acetaldehyde are formed. Compared with strong oxidizing agents such as peroxy acid, NCS used in the present application can obtain higher selectivity, thereby improving the yield.

[0064] Further, in step three, the oxidizing agent needs to be added in batches to ensure that the oxidation process is mild enough, greatly improving the selectivity of the reaction, avoiding over-oxidation, and improving the yield of the reaction. The number of times of adding the oxidizing agent in batches can be determined according to the specific needs and conditions of the experiment, and there is no fixed number of times. In the present application, the addition amount of the oxidizing agent NCS is further preferably 2.1 eq. From the perspective of improving the yield and reducing byproducts, the oxidizing agent is preferably added in four times, 1 eq in the first time, 0.5 eq in the second time, 0.5 eq in the third time, and 0.1 eq in the fourth time. The interval of each addition time can be appropriately adjusted according to the progress of the reaction, preferably more than one hour.

[0065] Further, in steps two and three of the present application, by adjusting the pH, the product can be maintained in an ionic state, which is further conducive to the precipitation of the product in a high yield and purity.

[0066] Examples

[0067] The following describes in detail the embodiments of the present application, it should be noted that the following described embodiments are exemplary, only for the explanation of the present application, and can not be understood as a limitation of the present application. In addition, if not specifically stated, all reagents used in the following examples are commercially available, or can be synthesized according to the text or known methods, and the reaction conditions not listed are also readily available to those skilled in the art.

[0068] Example 1

[0069] Preparation of 5-chloropyridine-3-sulfonic acid

[0070] Preparation of 3-(benzylsulfanyl)-5-chloropyridine

[0071]

[0072] Into a dry reaction flask, 3-chloro-5-fluoropyridine (55.0 g, 38 mmol), anhydrous potassium carbonate (6.3 g, 45.6 mmol), 50 ml DMF, benzyl mercaptan (4.7 g, 38 mmol) were added, after nitrogen protection, heated and stirred at 60°C for 5h, TLC (PE:EA=10:1) monitoring raw material disappearance, stop heating. The reaction system was cooled to room temperature, then 150 ml purified water was added, cooled to 5-15°C, then 10 mg seed crystal was added, solid was precipitated, temperature control 5-15°C stirring for 1h, filtration, filter cake was washed with 100 ml purified water, dried with oil pump at room temperature under vacuum to obtain 8.5 g of white solid, yield 94.9%, purity 98.1%.

[0073] Preparation of 3-(benzylsulfinyl)-5-chloropyridine

[0074]

[0075] Into a dry and clean 100 ml reaction flask, 3-(benzylsulfanyl)-5-chloropyridine (7.9 g, 33.5 mmol), NCS (4.9 g, 36.9 mmol), 32 ml glacial acetic acid, 11 ml purified water were added, after nitrogen protection, stirred at room temperature for 2h, TLC (PE:EA=10:1) monitoring raw material disappearance, the reaction system was adjusted to pH 4 with saturated sodium bicarbonate aqueous solution, white solid was precipitated, then 80 ml purified water was added, stirred at room temperature for 1h, filtered, the filter cake was washed with 100 ml purified water, dried to obtain 7.6 g of white solid, yield 90%, purity 99.2%.

[0076] Preparation of 5-chloropyridine-3-sulfonic acid

[0077]

[0078] In a dry reaction flask, 3-(benzylsulfinyl)-5-chloropyridine (7.0 g, 27.8 mmol), 42 ml acetic acid, 7 ml purified water, stirring at room temperature, nitrogen protection, NCS (7.8 g, 58.4 mmol) was added in four batches within 6 h, and after stirring at room temperature for 24 h, 50 ml 5% hydrochloric acid solution was added to the reaction system, the pH was 1, 50 ml dichloromethane was added, and the system was extracted and separated, the water phase was washed with 50 ml dichloromethane again, the water phase was kept, and the water phase was concentrated under reduced pressure at 60°C to precipitate a large amount of solid, then 50 ml acetone was added, stirred at room temperature for 1 h, filtered, the filter cake was washed with 10 ml acetone, and dried to obtain 4.0 g of white solid, the yield was 74.3%, and the purity was 98.6%.

[0079] Example 2

[0080] Preparation of 5-nitropyridine-2-sulfonic acid

[0081] Preparation of 2-(benzylsulfanyl)-5-nitropyridine

[0082]

[0083] In a dry reaction flask, 2-fluoro-5-nitropyridine (14.2 g, 100 mmol), anhydrous potassium carbonate (18.0 g, 130 mmol), 80 ml DMF, benzyl mercaptan (13.0 g, 105 mmol), nitrogen protection, stirring at 20-30°C for 2 h, TLC (PE:EA=19:1) monitoring raw material disappearance, and post-processing. The reaction system was cooled to 0-10°C, then 250 ml purified water was added, a large amount of solid was precipitated, stirring at 0-20°C for 2 h, filtration, the filter cake was washed with 100 ml purified water, and 45°C air drying was carried out to obtain 22.5 g of light yellow solid, the yield was 91.4%, and the liquid phase purity was 98.6%.

[0084] Preparation of 2-(benzylsulfinyl)-5-nitropyridine

[0085]

[0086] Into a dry and clean reaction flask, 2-(benzylsulfanyl)-5-nitropyridine (20.0 g, 81.2 mmol), NCS (11.9 g, 89.3 mmol), 100 ml glacial acetic acid, 20 ml purified water, after nitrogen protection, stirring at room temperature for 2 h, TLC (PE:EA = 19:1) monitoring raw material disappearance, the reaction system using saturated sodium bicarbonate aqueous solution to adjust the system pH to 4, precipitate white solid, then add 800 ml purified water, stirring at room temperature for 6 h, filtration, filter cake using 20 ml purified water, after drying to obtain 20 g of white solid 2-(benzylsulfinyl)-5-nitropyridine, yield 93.9%, purity 99.2%.

[0087] Preparation of 5-nitropyridine-2-sulfonic acid

[0088]

[0089] Into a dry reaction flask, 2-(benzylsulfinyl)-5-nitropyridine (15.0 g, 60.9 mmol), 90 ml acetic acid, 15 ml purified water, stirring at room temperature, nitrogen protection, NCS (17.1 g, 127.9 mmol) was added in four batches in 10 h, after adding stirring at room temperature for 20 h, add 100 ml purified water, add 70 ml dichloromethane, extraction and separation, the aqueous phase using 50 ml dichloromethane again, the water phase was concentrated under reduced pressure at 60 ℃ to precipitate a large amount of solid, then add 70 ml acetone, stirring at room temperature for 2 h, filtration, filter cake using 10 ml acetone, after drying to obtain 8.5 g white solid, yield 68.4%, purity 98.8%.

[0090] Example 3

[0091] Preparation of 5-bromopyridine-2-sulfonic acid

[0092] Preparation of 2-(benzylsulfanyl)-5-bromopyridine

[0093]

[0094] Into a dry reaction flask, 5-bromo-2-fluoropyridine (80 g, 454.6 mmol), anhydrous potassium carbonate (81.7 g, 591 mmol), 400 ml DMF, benzyl mercaptan (56.5 g, 454.6 mmol), after nitrogen protection, 20-30 °C stirring for 10 h, TLC (PE:EA = 50:1) monitoring raw material disappearance, post-processing. The reaction system is cooled to 0-10 °C, then 1500 ml of purified water is added, a large amount of solid is precipitated, the temperature is controlled at 0-20 °C and stirred for 2 h, filtered, the filter cake is washed with 100 ml of purified water, then washed with 100 ml of n-hexane (0 °C), and dried at 30 °C to obtain 120 g of white solid, the yield is 94.2%, and the liquid phase purity is 99.2%.

[0095] Preparation of 2-benzylsulfinyl-5-bromopyridine

[0096]

[0097] Into a dry and clean reaction flask, 2-(benzylsulfanyl)-5-bromopyridine (56.8 g, 202.6 mmol), NCS (29.8 g, 222.9 mmol), 360 ml glacial acetic acid, 60 ml purified water, after nitrogen protection, stirring at room temperature for 10 h, TLC (PE:EA = 19:1) monitoring raw material disappearance, the reaction system is adjusted to pH 4 with saturated sodium bicarbonate aqueous solution, white solid is precipitated, then 600 ml of purified water is added, stirred at room temperature for 2 h, filtered, the filter cake is washed with 100 ml of purified water, and dried to obtain 55 g of white solid 2-(benzylsulfinyl)-5-bromopyridine, the yield is 91.6%, and the purity is 99.3%.

[0098] Preparation of 5-bromopyridine-2-sulfonic acid

[0099]

[0100] Into a dry reaction flask, 2-(benzylsulfinyl)-5-bromopyridine (24 g, 81.0 mmol), 100 ml acetic acid, 15 ml purified water, stirring at room temperature, nitrogen protection, NCS (22.7 g, 170.1 mmol) is added in four batches within 8 h, after addition, stirring at room temperature for 24 h, then 50 ml of 5% hydrochloric acid solution is added to the reaction system, the pH of the system is 1, 100 ml of dichloromethane is added, extracted and separated, the aqueous phase is washed with 100 ml of dichloromethane again, the aqueous phase is concentrated under reduced pressure at 60 °C until a large amount of solid is precipitated, then 100 ml of acetonitrile is added, stirred at room temperature for 1 h, filtered, the filter cake is washed with 10 ml of acetonitrile, and dried to obtain 13 g of white solid, the yield is 67.4%, and the purity is 98.9%.

[0101] Example 4

[0102] In Example 1, except that the amount of NCS in the second step was changed to 4.9 g (33.5 mmol), i.e., 1.0 eq with respect to the amount of 3-(benzylthio)-5-chloropyridine, and the rest was operated identically to Example 1, 7.1 g of 3-(benzylsulfinyl)-5-chloropyridine was obtained, the yield was 89.9%, and the purity was 99.1%.

[0103] Except that the amount of NCS in the third step was changed to 7.4 g (55.6 mmol), i.e., 2.0 eq with respect to the amount of 3-(benzylsulfinyl)-5-chloropyridine, and the rest was operated identically to Example 1, 3.6 g of the final product was obtained, the yield was 65.0%, and the purity was 98.4%.

[0104] Example 5

[0105] In Example 1, except that the amount of NCS in the second step was changed to 5.4 g (40.2 mmol), i.e., 1.2 eq with respect to the amount of 3-(benzylthio)-5-chloropyridine, and the rest was operated identically to Example 1, 7.0 g of 3-(benzylsulfinyl)-5-chloropyridine was obtained, the yield was 88.6%, and the purity was 99.3%.

[0106] Except that the amount of NCS in the third step was changed to 8.2 g (61.2 mmol), i.e., 2.2 eq with respect to the amount of 3-(benzylsulfinyl)-5-chloropyridine, and the rest was operated identically to Example 1, 3.8 g of the final product was obtained, the yield was 70.6%, and the purity was 98.5%.

[0107] Comparative Example 1

[0108] In Example 1, as the purification step of the final product, instead of adjusting the pH to precipitate, 300 mL of ethyl acetate was extracted three times, and then the organic phase was washed with saturated brine until it became neutral, and then dried with anhydrous sodium sulfate, and concentrated to obtain the product, the yield was 100%, and the purity was 85%.

[0109] Comparative Example 2

[0110] In Example 1, except that the amount of NCS in the second step was changed to 0.9 eq with respect to 3-(benzylthio)-5-chloropyridine, and the rest was operated identically to Example 1 to obtain 3-(benzylsulfinyl)-5-chloropyridine, the yield was 80%, and the purity was 96%.

[0111] Except that the amount of NCS in the third step was changed to 1.9 eq with respect to 3-(benzylsulfinyl)-5-chloropyridine, and the rest was operated identically to Example 1 to obtain the final product, the yield was 45%, and the purity was 95%.

[0112] Comparative Example 3

[0113] In Example 1, except that the amount of NCS relative to 3-(benzylsulfanyl)-5- chloropyridine was changed to 1.3 eq in the second step, the rest was operated in the same manner as Example 1 to obtain 3-(benzylsulfinyl)-5-chloropyridine in a yield of 85% and a purity of 98%.

[0114] Except that the amount of NCS relative to 3-(benzylsulfinyl)-5-chloropyridine was changed to 2.3 eq in the third step, the rest was operated in the same manner as Example 1 to obtain the final product in a yield of 60% and a purity of 95%.

[0115] Comparative Example 4

[0116] In Example 1, except that all of the NCS was added at once instead of in batches in the third step, the rest was operated in the same manner as Example 1, but the target compound was not obtained.

[0117] In summary, the above description of the specific embodiments of the present application does not limit the present application, and those skilled in the art can make changes or modifications to the present application according to the present application, as long as they do not deviate from the spirit of the present application, and they should belong to the scope of the appended claims of the present application.

Claims

1. A method for producing a sulfonic acid compound, characterized by, A sulfonic acid compound is obtained by a three-step reaction from a fluoropyridine compound having an electron-withdrawing substituent as a starting material; The method comprises the following steps: (A) Substitution reaction: a fluoropyridine compound having an electron-withdrawing substituent is reacted with benzyl mercaptan in the presence of an inorganic base to obtain a benzylsulfanyl pyridine compound, (B) First oxidation reaction: after the benzylsulfanyl pyridine compound is mixed with NCS and reacted at room temperature under acidic conditions, the pH of the system is adjusted to precipitate a benzylsulfinyl pyridine compound, (C) Second oxidation and hydrolysis reaction: after NCS is added in batches and mixed with the benzylsulfinyl pyridine compound, the reaction is carried out under acidic conditions, and the sulfonic acid compound is obtained by crystallization. The chemical structural formula of the sulfonic acid compound is as follows: wherein R1 is an electron-withdrawing substituent, specifically selected from one of trifluoromethyl, nitro, cyano, and R2 is a sulfonic acid group.

2. The method for preparing the sulfonic acid compound according to claim 1, wherein in step (A), the substitution reaction is carried out at 20-90°C for 2-10h, and the corresponding benzylsulfanyl pyridine compound is obtained by crystallization and filtration.

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

4. The method for preparing the sulfonic acid compound according to claim 2, wherein in step (A), the benzylsulfanyl pyridine compound is obtained by crystallization by cooling.

5. The method for preparing the sulfonic acid compound according to claim 1 or 2, wherein in step (B), the amount of NCS is 1.0-1.2eq of the benzylsulfanyl pyridine compound.

6. The method for preparing the sulfonic acid compound according to claim 1 or 2, wherein in step (B), the benzylsulfanyl pyridine compound obtained in step (A) is stirred at room temperature in the presence of NCS in an organic acid solvent for 1-10h, and the corresponding benzylsulfinyl pyridine compound is obtained by adjusting the pH, crystallization and filtration.

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

8. The method for preparing the sulfonic acid compound according to claim 6, wherein in step (B), after the reaction is completed, the pH of the reaction system is adjusted to 4-6 for crystallization, and then purified water is added for stirring at room temperature for 1-6h to obtain the benzylsulfinyl pyridine compound.

9. The method for preparing the sulfonic acid compound according to claim 1 or 2, wherein in step (C), the amount of NCS is 2.0-2.2eq of the benzylsulfinyl pyridine compound.

10. The method for preparing the sulfonic acid compound according to claim 9, wherein in step (C), NCS is added in batches over 2-10h.

11. The method for preparing the sulfonic acid compound according to claim 10, wherein in step (C), the amount of NCS is 2.1eq of the benzylsulfinyl pyridine compound.

12. The method for preparing the sulfonic acid compound according to claim 11, wherein in step (C), NCS is added in batches over 2-10h. ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ 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 of claim 1 or 2, wherein the sulfonic acid compound is prepared by the steps of: (A) preparing a compound of the following formula: (B) reacting the compound of the formula obtained in step (A) with NCS in an acid solution to obtain a benzylsulfinylpyridine compound; (C) reacting the benzylsulfinylpyridine compound obtained in step (B) with NCS in an acid solution to obtain a sulfonic acid compound.

14. The method of claim 13, wherein the sulfonic acid compound is prepared by the steps of: (A) preparing a compound of the following formula: (B) reacting the compound of the formula obtained in step (A) with NCS in an acid solution to obtain a benzylsulfinylpyridine compound; (C) reacting the benzylsulfinylpyridine compound obtained in step (B) with NCS in an acid solution to obtain a sulfonic acid compound.

15. The method of claim 13 or 14, wherein, in step (C), the acid used in the reaction is formic acid, acetic acid, oxalic acid, or trifluoroacetic acid.

16. The method of claim 13 or 14, wherein, in step (C), the crystallization solvent is acetone or acetonitrile. ​

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