A method for synthesizing aryl sulfone compounds

Abstract

The present invention discloses a method for synthesizing aryl sulfone compounds. Using aromatic hydrocarbons and arylsulfonyl chlorides as raw materials, and silica gel sulfonic acid-trifluoromethanesulfonate as a composite catalyst, the reaction is carried out at 30-100 °C for 20-60 minutes. The obtained crude product is separated and purified by column chromatography to obtain the aryl sulfone compounds. The present invention uses recyclable silica gel sulfonic acid-trifluoromethanesulfonate as a composite catalyst, enabling the Friedel-Crafts sulfonylation reaction of aromatic hydrocarbons and arylsulfonyl chlorides to proceed under mild conditions of 30-100 °C with a short reaction time, low energy consumption, safety, environmental protection, high yield of the prepared aryl sulfone compounds, and is suitable for industrial production.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical intermediate preparation, and particularly to a method for synthesizing aryl sulfone compounds. Background Art

[0002] Sulfone compounds are a class of organic compounds with extremely wide applications. They can be used in the production of organic polymers, agrochemicals, bioactive substances, etc., and can also be used as key intermediates and building blocks for the synthesis of important compounds.

[0003] Aryl sulfones are a class of extremely important sulfur-containing compounds, which have been proven to have many good biological activities. For example, dapsone with high antibacterial activity can be combined with other anti-leprosy drugs for the treatment of various types of leprosy caused by Mycobacterium leprae, and can also be used for the treatment of other skin diseases; the important drug cariporide and the antidepressant CX157 are also aryl sulfone compounds. It can be seen that many aryl sulfone compounds have excellent pharmaceutical properties and have been widely used in clinical treatment.

[0004] So far, the synthesis methods of aryl sulfone compounds that have been developed mainly include: oxidation reaction of aryl sulfides, Friedel-Crafts sulfonylation reaction of aromatic hydrocarbons, coupling reaction of haloarenes or arylboronic acid compounds and arylsulfinic acids, etc. Among them, the Friedel-Crafts sulfonylation reaction is the most effective method for preparing aryl sulfone compounds.

[0005] However, in the process of implementing the technical solutions of the present invention by the inventors of the present application, it is found that the above technologies have at least the following technical problems: In the prior art, when using the Friedel-Crafts sulfonylation reaction to prepare aryl sulfone compounds, most researchers use solid superacids (Organic Chemistry, 2003, 23, 1438) and trifluoromethanesulfonic acid (Eur. J. Org. Chem. 2022, e202200477) as catalysts, and the reaction conditions all need to be carried out at a high temperature of 160°C for 24 hours. The reaction time is relatively long, and under such severe reaction conditions, isomers will inevitably be generated in the substituted aromatic hydrocarbons, resulting in low purity of the aryl sulfone compounds. The existence of a large number of isomers affects their application effects and increases the separation difficulty and cost. In view of the very important application prospects of aryl sulfone compounds, developing a method for efficiently synthesizing aryl sulfone compounds has important industrial application value. Summary of the Invention

[0006] The present invention provides a method for synthesizing aryl sulfone compounds, which solves the problems of high reaction temperature, long reaction time, and low product purity existing in the preparation of aryl sulfone compounds by using the Friedel-Crafts sulfonylation reaction in the prior art.

[0007] To solve the above technical problems, the present invention provides a method for synthesizing aryl sulfone compounds. Using aromatic hydrocarbons and arylsulfonyl chlorides as raw materials, and silica gel sulfonic acid-trifluoromethanesulfonate as a composite catalyst, the reaction is carried out at 30-100 °C for 20-60 min. The obtained crude product is separated and purified by column chromatography to obtain the aryl sulfone compounds.

[0008] In a preferred embodiment of the present invention, the molar ratio of the aromatic hydrocarbon and the arylsulfonyl chloride charged is 1:1-1.2.

[0009] In a preferred embodiment of the present invention, the molar ratio of the aromatic hydrocarbon, the arylsulfonyl chloride and the composite catalyst charged is 1:1-1.2:0.1-0.4.

[0010] In a preferred embodiment of the present invention, in the composite catalyst, the molar ratio of the silica gel sulfonic acid and the trifluoromethanesulfonate is 1:1.

[0011] In a preferred embodiment of the present invention, the preparation method of the composite catalyst is as follows: silica gel and chlorosulfonic acid are added to a Schlenk reaction tube to in-situ prepare silica gel sulfonic acid, and then trifluoromethanesulfonate is added and stirred evenly.

[0012] In a preferred embodiment of the present invention, the trifluoromethanesulfonate includes at least one of aluminum trifluoromethanesulfonate, sodium trifluoromethanesulfonate, lithium trifluoromethanesulfonate, copper trifluoromethanesulfonate, indium trifluoromethanesulfonate, silver trifluoromethanesulfonate, zinc trifluoromethanesulfonate, magnesium trifluoromethanesulfonate, tin trifluoromethanesulfonate, scandium trifluoromethanesulfonate, nickel trifluoromethanesulfonate, bismuth trifluoromethanesulfonate or lanthanum trifluoromethanesulfonate.

[0013] In a preferred embodiment of the present invention, the eluent used for column chromatography separation is ethyl acetate and petroleum ether.

[0014] In a preferred embodiment of the present invention, the volume ratio of the ethyl acetate and the petroleum ether is 1:20 to 1:5.

[0015] The beneficial effects of the present invention are as follows: The method for synthesizing aryl sulfone compounds of the present invention uses recyclable silica gel sulfonic acid-trifluoromethanesulfonate as a composite catalyst, enabling the Friedel-Crafts sulfonylation reaction of aromatic hydrocarbons and arylsulfonyl chlorides to be carried out under mild conditions of 30-100 °C with a short reaction time, low energy consumption, safety, environmental protection, high yield of the prepared aryl sulfone compounds, and being suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 is the nuclear magnetic spectrum of 4-chloro-4'-bromo-diphenyl sulfone prepared in Example 2 of the present invention. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0017] The following describes in detail the preferred embodiments of the present invention with reference to the accompanying drawings, so that the advantages and features of the present invention can be more easily understood by those skilled in the art, thereby making a clearer and more definite definition of the protection scope of the present invention.

[0018] Please refer to Figure 1 , the embodiments of the present invention include:

[0019] The present invention discloses a method for synthesizing aryl sulfone compounds. Creatively, silica sulfonic acid-trifluoromethanesulfonate is used as a composite catalyst. This silica sulfonic acid-trifluoromethanesulfonate composite catalyst can effectively reduce the reaction activation energy, enabling the Friedel-Crafts sulfonylation reaction of aromatic hydrocarbons and arylsulfonyl chlorides to proceed under mild conditions of 30-100 °C. The yield of the obtained aryl sulfone compounds is high, above 96%.

[0020] The synthesis route is as follows:

[0021]

[0022] Among them, X is H or Cl, and Y is H, halogen or alkyl.

[0023] Example 1

[0024] The synthesis of diphenyl sulfone, the chemical reaction equation is as follows:

[0025]

[0026] Add 5 grams of dry silica gel to a Schlenk reaction tube, inject chlorosulfonic acid (1 mmol) using a syringe, stir for 10 minutes to in-situ prepare silica sulfonic acid; add scandium trifluoromethanesulfonate (1 mmol), stir evenly, and then add benzenesulfonyl chloride (10 mmol) and benzene (12 mmol); heat to 70 °C and react for 45 minutes. After gas phase detection, the reaction is completed, cooled to room temperature, extracted with dichloromethane, the solid catalyst is recovered by suction filtration, the filtrate is concentrated, and the residue is purified by column chromatography (eluent: ethyl acetate: petroleum ether = 1:20 → 1:5) to obtain 2.14 grams of product (yield 98%); 1HNMR (400 MHz, CDCl3): 7.96 - 7.94 (m, 2H), 7.59 - 7.55 (m, 2H), 7.52 - 7.27 (m, 4H).

[0027] Example 2

[0028] The synthesis of 4-chloro-4'-bromo-diphenyl sulfone, the chemical reaction equation is as follows:

[0029]

[0030] Add 5 g of dry silica gel to a Schlenk reaction tube. Inject chlorosulfonic acid (1 mmol) using a syringe and stir for 10 minutes to in-situ prepare silica sulfonic acid. Add indium trifluoromethanesulfonate (1 mmol), stir evenly, then add p-chlorobenzenesulfonyl chloride (10 mmol) and bromobenzene (12 mmol). Heat to 80 °C and react for 30 minutes. After detecting the end of the reaction by gas chromatography, cool to room temperature, extract with dichloromethane, filter to recover the solid catalyst, concentrate the filtrate, and purify the residue by column chromatography (eluent: ethyl acetate: petroleum ether = 1:20 → 1:5) to obtain 3.19 g of the product (yield 96%); 1H NMR (400 MHz, CDCl3): 7.86 (d, J = 4 Hz, 2H), 7.79 (d, J = 4 Hz, 2H), 7.66 (d, J = 4 Hz, 2H), 7.49 (d, J = 4 Hz, 2H). The NMR spectrum is as attached Figure 1 as shown.

[0031] Example 3

[0032] Synthesis of 4-fluoro-4'-chloro-diphenyl sulfone. The chemical reaction equation is as follows:

[0033]

[0034] Add 5 g of dry silica gel to a Schlenk reaction tube. Inject chlorosulfonic acid (1 mmol) using a syringe and stir for 10 minutes to in-situ prepare silica sulfonic acid. Add copper trifluoromethanesulfonate (1 mmol), stir evenly, then add p-chlorobenzenesulfonyl chloride (10 mmol) and fluorobenzene (12 mmol). Heat to 80 °C and react for 45 minutes. After detecting the end of the reaction by gas chromatography, cool to room temperature, extract with dichloromethane, filter to recover the solid catalyst, concentrate the filtrate, and purify the residue by column chromatography (eluent: ethyl acetate: petroleum ether = 1:20 → 1:5) to obtain 2.63 g of the product (yield 97%); 1H NMR (400 MHz, CDCl3): 7.98 - 7.91 (m, 2H), 7.89 - 7.82 (m, 2H), 7.51 - 7.45 (m, 2H), 7.24 - 7.15 (m, 2H).

[0035] Example 4

[0036] Synthesis of 4-chloro-diphenyl sulfone. The chemical reaction equation is as follows:

[0037]

[0038] Add 5 g of dry silica gel to a Schlenk reaction tube. Inject chlorosulfonic acid (1 mmol) using a syringe and stir for 10 minutes to in-situ prepare silica sulfonic acid. Add indium trifluoromethanesulfonate (1 mmol), stir evenly, then add p-chlorobenzenesulfonyl chloride (10 mmol) and benzene (12 mmol). Heat to 50 °C and react for 60 minutes. When gas-phase detection indicates the reaction is complete, cool to room temperature, extract with dichloromethane, filter to recover the solid catalyst by suction, concentrate the filtrate, and purify the residue by column chromatography (eluent: ethyl acetate: petroleum ether = 1:20 → 1:5) to obtain 2.48 g of product (yield 98%); 1H NMR (400 MHz, CDCl3): 7.94 - 7.91 (m, 2H), 7.90 - 7.86 (m, 2H), 7.61 - 7.58 (m, 1H), 7.61 - 7.46 (m, 4H).

[0039] Example 5

[0040] Synthesis of 4-fluoro-diphenyl sulfone, the chemical reaction equation is as follows:

[0041]

[0042] Add 5 g of dry silica gel to a Schlenk reaction tube. Inject chlorosulfonic acid (1 mmol) using a syringe and stir for 10 minutes to in-situ prepare silica sulfonic acid. Add bismuth trifluoromethanesulfonate (1 mmol), stir evenly, then add benzenesulfonyl chloride (10 mmol) and fluorobenzene (12 mmol). Heat to 80 °C and react for 30 minutes. When gas-phase detection indicates the reaction is complete, cool to room temperature, extract with dichloromethane, filter to recover the solid catalyst by suction, concentrate the filtrate, and purify the residue by column chromatography (eluent: ethyl acetate: petroleum ether = 1:20 → 1:5) to obtain 2.31 g of product (yield 98%); 1H NMR (400 MHz, CDCl3): 7.98 - 7.86 (m, 4H), 7.60 - 7.54 (m, 1H), 7.52 - 7.46 (m, 2H), 7.22 - 7.10 (m, 2H).

[0043] Example 6

[0044] Synthesis of 4-bromo-diphenyl sulfone, the chemical reaction equation is as follows:

[0045]

[0046] Add 5 g of dry silica gel to a Schlenk reaction tube. Inject chlorosulfonic acid (1 mmol) using a syringe and stir for 10 minutes to in-situ prepare silica sulfonic acid. Add bismuth trifluoromethanesulfonate (1 mmol), stir evenly, then add benzenesulfonyl chloride (10 mmol) and bromobenzene (12 mmol). Heat to 100 °C and react for 20 minutes. After detecting the end of the reaction by gas chromatography, cool to room temperature, extract with dichloromethane, filter to recover the solid catalyst, concentrate the filtrate, and purify the residue by column chromatography (eluent: ethyl acetate: petroleum ether = 1:20 → 1:5) to obtain 2.91 g of the product (yield 98%); 1H NMR (400 MHz, CDCl3): 7.94 - 7.91 (m, 2H), 7.82 - 7.79 (m, 2H), 7.65 - 7.61 (m, 2H), 7.60 - 7.55 (m, 1H), 7.53 - 7.48 (m, 2H).

[0047] Example 7

[0048] Synthesis of 4-methyl-diphenyl sulfone, the chemical reaction equation is as follows:

[0049]

[0050] Add 5 g of dry silica gel to a Schlenk reaction tube. Inject chlorosulfonic acid (1 mmol) using a syringe and stir for 10 minutes to in-situ prepare silica sulfonic acid. Add bismuth trifluoromethanesulfonate (1 mmol), stir evenly, then add benzenesulfonyl chloride (10 mmol) and toluene (12 mmol). Heat to 50 °C and react for 30 minutes. After detecting the end of the reaction by gas chromatography, cool to room temperature, extract with dichloromethane, filter to recover the solid catalyst, concentrate the filtrate, and purify the residue by column chromatography (eluent: ethyl acetate: petroleum ether = 1:20 → 1:5) to obtain 2.25 g of the product (yield 97%); 1H NMR (400 MHz, CDCl3): 7.94 - 7.90 (m, 2H), 7.85 - 7.80 (m, 2H), 7.59 - 7.45 (m, 3H), 7.30 - 7.28 (m, 2H), 2.39 (s, 2H).

[0051] Example 8

[0052] Synthesis of 4-methyl-4'-chloro-diphenyl sulfone, the chemical reaction equation is as follows:

[0053]

[0054] Add 5 g of dry silica gel to a Schlenk reaction tube, inject chlorosulfonic acid (1 mmol) using a syringe, stir for 10 minutes to in-situ prepare silica sulfonic acid; add bismuth trifluoromethanesulfonate (1 mmol), stir evenly, then add p-chlorobenzenesulfonyl chloride (10 mmol) and toluene (12 mmol); heat to 60 °C and react for 30 minutes, detect the end of the reaction by gas phase, cool to room temperature, extract with dichloromethane, filter to recover the solid catalyst, concentrate the filtrate, and purify the residue by column chromatography (eluent: ethyl acetate: petroleum ether = 1:20 → 1:5) to obtain 2.59 g of product (yield 97%); 1H NMR (400 MHz, CDCl3): 7.89 - 7.86 (m, 2H), 7.82 - 7.78 (m, 2H), 7.46 - 7.42 (m, 2H), 7.32 - 7.29 (m, 2H), 2.40 (s, 2H).

[0055] Example 9

[0056] Compared with Example 1, the composite catalyst used is the catalyst separated and recovered in Example 1. 2.13 g of product was obtained by the reaction, and the yield is equivalent to that of Example 1.

[0057] Example 10

[0058] Compared with Example 2, the composite catalyst used is the catalyst separated and recovered in Example 2. 3.17 g of product was obtained by the reaction, and the yield is equivalent to that of Example 2.

[0059] Example 11

[0060] Compared with Example 8, the composite catalyst used is the catalyst separated and recovered in Example 8. 2.58 g of product was obtained by the reaction, and the yield is equivalent to that of Example 8.

[0061] The present invention has the following beneficial effects:

[0062] 1. Creatively using silica sulfonic acid - trifluoromethanesulfonate as a composite catalyst can effectively reduce the reaction activation energy, enabling the Friedel - Crafts sulfonylation reaction of aromatic hydrocarbons and arylsulfonyl chlorides to proceed under mild conditions, with a short reaction time, effectively avoiding the generation of by - products and reducing the content of isomers, thereby improving the purity and yield of aryl sulfone compounds;

[0063] 2. The solubility difference between the product and the composite catalyst of the present invention in organic solvents is large, which is conducive to the effective separation of the product and helps to improve the yield of the product;

[0064] 3. The composite catalyst used can be recovered and recycled, effectively saving costs and being green and environmentally friendly;

[0065] 4. The synthesis method of the present invention is simple and convenient to operate, has low energy consumption, is safe and environmentally friendly, and has a high yield of aryl sulfone compounds.

[0066] The above are only embodiments of the present invention, and do not limit the patent scope of the present invention. Any equivalent structure or equivalent process transformation made by using the content of the specification and drawings of the present invention, or directly or indirectly applied in other related technical fields, shall be similarly included in the patent protection scope of the present invention.

Claims

1. A method for synthesizing aryl sulfone compounds, characterized in that, using aromatic hydrocarbons and arylsulfonyl chlorides as raw materials, and silica gel sulfonic acid-trifluoromethanesulfonate as a composite catalyst, reacting at 30-100 °C for 20-60 min, and the obtained crude product is separated and purified by column chromatography to obtain the aryl sulfone compounds; the trifluoromethanesulfonate includes at least one of copper trifluoromethanesulfonate, indium trifluoromethanesulfonate, silver trifluoromethanesulfonate, zinc trifluoromethanesulfonate, tin trifluoromethanesulfonate, scandium trifluoromethanesulfonate, nickel trifluoromethanesulfonate or bismuth trifluoromethanesulfonate.

2. The method for synthesizing aryl sulfone compounds according to claim 1, characterized in that, the molar ratio of the aromatic hydrocarbon and the arylsulfonyl chloride charged is 1:1-1.

2.

3. The method for synthesizing aryl sulfone compounds according to claim 2, characterized in that, the molar ratio of the aromatic hydrocarbon, the arylsulfonyl chloride and the composite catalyst charged is 1:1-1.2:0.1-0.

4.

4. The method for synthesizing aryl sulfone compounds according to claim 3, characterized in that, in the composite catalyst, the molar ratio of the silica gel sulfonic acid and the trifluoromethanesulfonate is 1:

1.

5. The method for synthesizing aryl sulfone compounds according to claim 4, characterized in that, the preparation method of the composite catalyst is: adding silica gel and chlorosulfonic acid into a Schlenk reaction tube, in-situ reacting to prepare silica gel sulfonic acid, and then adding trifluoromethanesulfonate and stirring evenly.

6. The method for synthesizing aryl sulfone compounds according to claim 1, characterized in that, the eluent used for column chromatography separation is ethyl acetate and petroleum ether.

7. The method for synthesizing aryl sulfone compounds according to claim 6, characterized in that, the volume ratio of the ethyl acetate and the petroleum ether is 1:20 to 1:5.

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