Preparation method of 2, 3, 5, 6-tetrafluorophenyl-1, 4-disulfonyl chloride

Abstract

The invention discloses a preparation method of 2, 3, 5, 6-tetrafluorophenyl-1, 4-disulfonyl chloride, and belongs to the technical field of organic intermediates. The preparation method comprises the following steps: taking 2, 3, 5, 6-tetrafluorop-phenylenediamine, DABSO and a hydrochloric acid aqueous solution as raw materials, and reacting in acetonitrile in the presence of a catalyst and tert-butyl nitrite to obtain 2, 3, 5, 6-tetrafluorophenyl-1, 4-disulfonyl chloride. In the method, the copper porphyrin catalyst is the key, the catalytic effect is good, and the yield is obviously reduced when the copper porphyrin catalyst is replaced with other copper catalysts. All the raw materials can be conveniently purchased on the market, the target product is synthesized through a one-step method, three wastes are few, the yield is high, and industrial production is easy.

Description

Technical Field

[0001] The invention relates to a method for preparing 2,3,5,6-tetrafluorobenzene-1,4-disulfonyl chloride, and belongs to the technical field of organic intermediate preparation. Background Art

[0002] 2,3,5,6-Tetrafluorobenzene-1,4-disulfonyl chloride is primarily used in organic synthesis and the preparation of pharmaceutical intermediates. It is an important raw material for organic synthesis and is commonly used in the synthesis of various organic compounds, particularly in the pharmaceutical and pesticide fields. It can also serve as an intermediate in the synthesis of a variety of drugs.

[0003] For this product, after searching the literature on existing technologies, the current synthesis methods mainly include the following one.

[0004] The literature [Dalton Trans., 2011, 40, 3128] reports that 2,3,5,6-tetrafluoro-1,4-hydroquinone is used as the raw material, undergoes esterification, high-temperature isomerization reaction, and finally oxidative chlorination to produce 2,3,5,6-tetrafluorobenzene-1,4-disulfonyl chloride. The reaction formula is as follows:

[0005]

[0006] The above reaction methods have the disadvantages of complicated steps, high temperature reaction and low yield.

[0007] Therefore, it is necessary to conduct in-depth research on the synthesis route of 2,3,5,6-tetrafluorobenzene-1,4-disulfonyl chloride to provide a simple, safe, stable and economical process route with easily available raw materials to meet the growing market demand in the future. Summary of the Invention

[0008] The technical problem to be solved by the present invention is to provide a method for preparing 2,3,5,6-tetrafluorobenzene-1,4-disulfonyl chloride. This method comprises the following steps: 2,3,5,6-tetrafluoro-p-phenylenediamine, DABSO, and aqueous hydrochloric acid are reacted in acetonitrile in the presence of a catalyst and tert-butyl nitrite to obtain 2,3,5,6-tetrafluorobenzene-1,4-disulfonyl chloride. In this method, a copper porphyrin catalyst is key, providing excellent catalytic effects. Substituting other copper catalysts significantly reduces the yield. The target product is synthesized in a one-step process.

[0009] In order to achieve the above object, the technical solution of the present invention is expressed as follows using the reaction equation:

[0010]

[0011] The present invention provides a method for preparing 2,3,5,6-tetrafluorobenzene-1,4-disulfonyl chloride, comprising the following steps: using 2,3,5,6-tetrafluoro-p-phenylenediamine, DABSO and a hydrochloric acid aqueous solution as raw materials, reacting in an organic solvent in the presence of a catalyst and tert-butyl nitrite to obtain 2,3,5,6-tetrafluorobenzene-1,4-disulfonyl chloride.

[0012] Preferably, in the above steps, the organic solvent is acetonitrile.

[0013] It should be noted that acetonitrile is easy to post-process, separate into layers and recycle as an organic solvent, while other types of solvents will not produce good reaction results. Therefore, acetonitrile was selected as the reaction solvent.

[0014] Preferably, in the above steps, the catalyst is selected from one or two of copper chloride, tetrakis-p-methoxyporphyrin copper, tetrakis-p-phenylporphyrin copper or tetrakis-p-chlorophenylporphyrin copper.

[0015] Preferably, in the above step, the acid is 30-37% hydrochloric acid. It should be noted that the hydrochloric acid should be added slowly and dropwise. Adding hydrochloric acid releases heat, causing the temperature to rise. To ensure the reaction occurs at room temperature, the hydrochloric acid should be added slowly and dropwise.

[0016] Preferably, in the above steps, the molar ratio of the 2,3,5,6-tetrafluoro-p-diphenylamine, DABSO, catalyst, acid and tert-butyl nitrite is 1:1-1.5:0.01-0.03:2.6-3.3:2-2.5.

[0017] Preferably, in the above steps, the reaction is carried out at 0-30°C, with room temperature being the optimal temperature condition.

[0018] Beneficial effects of the present invention:

[0019] A. The present invention develops a simple and practical synthesis route and adopts efficient and readily available catalysts. The route has low production cost, reasonable design and less three wastes.

[0020] B. Using 2,3,5,6-tetrafluoro-p-diphenylamine as the raw material avoids the fluorination step. The reaction uses a porphyrin copper catalyst, which has a good catalytic effect, reduces the formation of by-products, and synthesizes the target product in one step, thereby improving efficiency. Specific embodiments

[0021] Although the present invention has been described in detail by way of preferred embodiments, the present invention is not limited thereto. Without departing from the spirit and essence of the present invention, a person of ordinary skill in the art may make various equivalent modifications or substitutions to the embodiments of the present invention, and such modifications or substitutions shall be within the scope of the present invention. Any person skilled in the art who can easily conceive of changes or substitutions within the technical scope disclosed in the present invention shall be included within the scope of protection of the present invention. Therefore, the scope of protection of the present invention shall be based on the scope of protection described in the claims.

[0022] Example 1

[0023]

[0024] Under nitrogen, 2,3,5,6-tetrafluoro-p-diphenylamine (18 g, 0.1 mol), DABSO (28.8 g, 0.12 mol), and cupric chloride (0.4 g, 0.003 mol) were mixed in 400 mL of acetonitrile. The system temperature was maintained below 25°C, and 37% hydrochloric acid (29.6 g, 0.3 mol) was slowly added, followed by t-BuONO (22.7 g, 0.22 mol). After complete addition, the mixture was allowed to react at room temperature for 13 hours. The mixture was extracted twice with 200 mL of dichloromethane and concentrated. The crude product was purified by column chromatography using ethyl acetate / petroleum ether (v / v = 1:3-8) as eluent to obtain 18.1 g of 2,3,5,6-tetrafluorobenzene-1,4-disulfonyl chloride in a 52% yield with 98.1% HPLC purity, consistent with the standard sample. (The yield of byproduct 1 by NMR analysis of the mother liquor and external standard was 25%, and the yield of byproduct 2 was 8%). 2,3,5,6-Tetrafluorobenzene-1,4-disulfonyl chloride (melting point 154.8°C, colorless solid). 13 C-NMR (125MHz, CDCl3): 128.2-128.3 (m, CS), 144.2 (dm, CF) ppm. 19 F-NMR (470MHz, CDCl3): -129.81ppm.

[0025] Example 2

[0026] Under nitrogen, 2,3,5,6-tetrafluoro-p-diphenylamine (18 g, 0.1 mol), DABSO (36 g, 0.15 mol), and copper tetrakis-p-methoxyporphyrin (2.4 g, 0.003 mol) were mixed in 400 ml of acetonitrile. The temperature was maintained below 25°C, and 33% hydrochloric acid (33.2 g, 0.3 mol) was slowly added, followed by t-BuONO (22.7 g, 0.22 mol). After completion of the addition, the mixture was allowed to react at room temperature for 12 hours. The mixture was extracted twice with 200 mL of dichloromethane and concentrated. The crude product was purified by column chromatography using ethyl acetate / petroleum ether (v / v = 1:3-8) as the eluent to obtain 24.3 g of 2,3,5,6-tetrafluorobenzene-1,4-disulfonyl chloride in a 70% yield with an HPLC purity of 98.4%. (The yield of the mother liquor byproduct 1, as determined by NMR analysis and external standard, was 13%).

[0027] Example 3

[0028] Under nitrogen, 2,3,5,6-tetrafluoro-p-diphenylamine (18 g, 0.1 mol), DABSO (28.8 g, 0.12 mol), and copper tetrakis-p-chlorophenylporphyrin (1.6 g, 0.002 mol) were mixed in 400 ml of acetonitrile. The system temperature was maintained below 25°C, and 37% hydrochloric acid (29.6 g, 0.3 mol) was slowly added, followed by t-BuONO (22.7 g, 0.22 mol). After completion of the addition, the mixture was allowed to react at room temperature for 10 hours. The mixture was extracted twice with 200 mL of dichloromethane and concentrated. The crude product was purified by column chromatography using ethyl acetate / petroleum ether (v / v = 1:3-8) as the eluent to obtain 28.8 g of 2,3,5,6-tetrafluorobenzene-1,4-disulfonyl chloride in an 83% yield with an HPLC purity of 98.8%. (The yield of the mother liquor byproduct 1 was 5% as determined by NMR analysis of the external standard.)

[0029] Example 4

[0030] Under nitrogen, 2,3,5,6-tetrafluoro-p-diphenylamine (18 g, 0.1 mol), DABSO (31.2 g, 0.13 mol), and copper tetraphenylporphyrin (2.0 g, 0.003 mol) were mixed in 400 ml of acetonitrile. The temperature was maintained below 25°C, and 37% hydrochloric acid (29.6 g, 0.3 mol) was slowly added, followed by t-BuONO (22.7 g, 0.22 mol). After completion of the addition, the mixture was allowed to react at room temperature for 11 hours. The mixture was extracted twice with 200 mL of dichloromethane and concentrated. The crude product was purified by column chromatography using ethyl acetate / petroleum ether (v / v = 1:3-8) as the eluent to obtain 27.1 g of 2,3,5,6-tetrafluorobenzene-1,4-disulfonyl chloride in a 78% yield with an HPLC purity of 98.5%. (The yield of the mother liquor byproduct 1 was 8% as determined by NMR analysis of the external standard.)

[0031] Example 5

[0032] Under nitrogen protection, 2,3,5,6-tetrafluoro-p-diphenylamine (18 g, 0.1 mol), DABSO (28.8 g, 0.12 mol), copper chloride (0.13 g, 0.001 mol) and tetrakis-p-chlorophenylporphyrin copper (0.81 g, 0.001 mol) were mixed in 400 ml of acetonitrile. The system temperature was controlled to be less than 25°C. 37% hydrochloric acid (29.6 g, 0.3 mol) was slowly added, followed by t-BuONO (22.7 g, 0.22 mol). After the addition was complete, the mixture was reacted at room temperature for 15 hours, extracted twice with 200 mL of dichloromethane, and concentrated. The crude product was purified by column chromatography with ethyl acetate / petroleum ether (v / v = 1:3-8) as the eluent to obtain 25.3 g of 2,3,5,6-tetrafluorobenzene-1,4-disulfonyl chloride in a yield of 73% and an HPLC purity of 98.3%. (The yield of mother liquor NMR external standard by-product 1 is 10%).

[0033] The above description is only a preferred specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any technician familiar with the technical field, within the technical scope disclosed by the present invention, who makes equivalent replacements or changes based on the technical solution and inventive concept of the present invention, should be covered by the scope of protection of the present invention.

Claims

1. A method for preparing 2,3,5,6-tetrafluorobenzene-1,4-disulfonyl chloride, characterized in that: The steps include: 2,3,5,6-tetrafluoro-p-phenylenediamine, DABSO and hydrochloric acid aqueous solution are used as raw materials and react in an organic solvent in the presence of a catalyst and tert-butyl nitrite to obtain 2,3,5,6-tetrafluorobenzene-1,4-disulfonyl chloride.

2. 2,3,5,6-tetrafluorobenzene-1,4-disulfonyl chloride according to claim 1, characterized in that: The organic solvent is acetonitrile.

3. The method for preparing 2,3,5,6-tetrafluorobenzene-1,4-disulfonyl chloride according to claim 1, characterized in that: The catalyst is selected from one or two of copper chloride, tetrakis-p-methoxyporphyrin copper, tetrakis-p-phenylporphyrin copper or tetrakis-p-chlorophenylporphyrin copper.

4. The method for preparing 2,3,5,6-tetrafluorobenzene-1,4-disulfonyl chloride according to claim 1, characterized in that: The hydrochloric acid aqueous solution is 30-37% hydrochloric acid.

5. The method for preparing 2,3,5,6-tetrafluorobenzene-1,4-disulfonyl chloride according to claim 1, characterized in that: The molar ratio of the 2,3,5,6-tetrafluoro-p-diphenylamine, DABSO, catalyst, acid and tert-butyl nitrite is 1:1-1.5:0.01-0.03:2.6-3.3:2-2.

5.

6. The method for preparing 2,3,5,6-tetrafluorobenzene-1,4-disulfonyl chloride according to claim 1, characterized in that: The reaction is carried out at 0-30°C.

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