Preparation method of 1-fluoro-2-trifluoromethylsulfonyl benzene

Abstract

The invention discloses a preparation method of 1-fluoro-2-trifluoromethylsulfonyl benzene, and belongs to the technical field of organic intermediates. The preparation method comprises the following steps: reacting phenol serving as a raw material with trifluoromethanesulfonic anhydride to generate an intermediate 1; then carrying out Thia-Fries rearrangement under the action of LDA, and then reacting with trifluoromethanesulfonic anhydride to generate an intermediate 2; then, the intermediate 2 reacts with a fluorinating reagent, and the 1-fluoro-2-trifluoromethylsulfonyl benzene is generated. In the method, all the raw materials can be conveniently purchased on the market, and each step of reaction is simple and convenient in process, high in yield and easy for industrial production.

Description

Technical Field

[0001] The invention relates to a preparation method of 1-fluoro-2-trifluoromethanesulfonylbenzene, belonging to the technical field of organic intermediate preparation. Background Art

[0002] 1-Fluoro-2-trifluoromethanesulfonylbenzene (CAS No: 2358-41-0) is an organic compound with multiple uses, playing an important role in industry, organic synthesis, etc. It can be used as a starting material for the synthesis of drugs, pesticides, and liquid crystal compounds.

[0003] For this product, after literature search of existing technologies, the current synthesis methods are mainly the following.

[0004] Patents and literature [CN111410666A; WO2020140956A; Journal of Medical Chemistry, 2008, 51, 6902] report that 2-fluorothiophenol is used as a raw material, and 1-fluoro-2-trifluoromethanesulfonylbenzene is generated through trifluoromethylation and oxidation. The reaction formula is as follows:

[0005]

[0006] Patents and literature [CN109851535 A; Synthesis, 2008, 15, 2398; Journal of Fluorine Chemistry, 1991, 52, 295; Chemical Communications, 2010, 46, 8020] report that 1-nitro-2-trifluoromethanesulfonylbenzene (or 1-chloro-2-trifluoromethanesulfonylbenzene) is used as a raw material and reacts with a fluorination agent such as potassium fluoride at high temperature to synthesize 1-fluoro-2-trifluoromethanesulfonylbenzene. The reaction formula is as follows:

[0007]

[0008] In the methods provided in the above documents, expensive ruthenium catalysts or relatively expensive raw materials are used for the reaction, which is not conducive to the promotion and application of 1-fluoro-2-trifluoromethanesulfonylbenzene products.

[0009] Therefore, it is necessary to conduct in-depth research on the synthesis route of 1-fluoro-2-trifluoromethanesulfonylbenzene to provide a better, simple, safe, stable and economical process route with readily available raw materials to meet the growing market demand. Summary of the invention

[0010] The technical problem to be solved by the present invention is to provide a method for preparing 1-fluoro-2-trifluoromethanesulfonylbenzene.

[0011] The objective of the present invention is achieved through the following technical solutions, and the reaction equation is expressed as follows:

[0012] The steps include:

[0013] A. Phenol and trifluoromethanesulfonic anhydride are mixed in a base to generate intermediate 1;

[0014] B. Mixing intermediate 1 and LDA in THF, reacting under low temperature conditions, and then reacting with trifluoromethanesulfonic anhydride to generate intermediate 2;

[0015] C. Mix the intermediate 2 with a fluorination agent in a solvent and react at elevated temperature to generate 1-fluoro-2-trifluoromethanesulfonylbenzene.

[0016] Preferably, in the above step A, the base is selected from diisopropylethylamine or pyridine.

[0017] Preferably, in the above step A, the molar ratio of phenol to trifluoromethanesulfonic anhydride is 1:1-1.2.

[0018] Preferably, in the above step B, the low temperature condition is -78-0°C.

[0019] Preferably, in the above step B, the molar ratio of the intermediate 1, LDA and trifluoromethanesulfonic anhydride is 1:1-1.1:1-1.1.

[0020] Preferably, in the above step C, the fluorination agent is selected from one or both of CsF and tetramethylammonium fluoride.

[0021] Preferably, in the above step C, the solvent is sulfolane.

[0022] Preferably, in the above step C, the temperature is raised to 80-120°C.

[0023] Preferably, in the above step C, the molar ratio of the intermediate 2 to the fluorination agent is 1:1-1.5.

[0024] Beneficial effects of the present invention:

[0025] A. The present invention develops a simple and practical synthesis route, using phenol with relatively low cost as raw material, with low production cost, reasonable design and less three wastes.

[0026] B. Using phenyl trifluoromethanesulfonate to carry out Thia-Fries rearrangement reaction to obtain 2-trifluoromethanesulfonylphenol, and simultaneously carrying out trifluoromethanesulfonic anhydride and phenolic group reaction, thus reducing steps and improving efficiency.

[0027] C. The present invention uses phenyl trifluoromethanesulfonate and a fluorinating agent to directly carry out fluorine substitution. At the same time, due to the strong trifluoromethanesulfonyl electron-withdrawing group on the benzene ring, the fluorination yield is greatly improved and the cost is reduced. Specific embodiments

[0028] 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 these modifications or substitutions shall be within the scope of the present invention. Any person of ordinary skill in the art may easily think of changes or substitutions within the technical scope disclosed by the present invention, and these shall be within the scope of protection of the present invention. Therefore, the scope of protection of the present invention shall be subject to the scope of protection described in the claims.

[0029] Example 1

[0030]

[0031] Under nitrogen protection, phenol (9.4 g, 0.1 mol) was mixed in 200 mL of pyridine, cooled to 0°C, and trifluoromethanesulfonic anhydride (31 g, 0.11 mol) was slowly added dropwise. After the addition was complete, the mixture was heated to room temperature and reacted for 4 hours. After the reaction was complete, the mixture was concentrated, and the crude product was slurried with n-hexane, filtered, and the filtrate was concentrated to obtain intermediate 1, 21.5 g, with a yield of 95%, and HPLC 98.8%. 1 HNMR(400MHz, CDCl3):7.49-7.45(m,2H),7.41-7.36(m,1H),7.30-7.26(m,2H).

[0032] Example 2

[0033]

[0034] Under argon protection, 2,2,6,6-tetramethylpiperidinium lithium (15.5 g, 0.105 mol) was added to 105 mL of tetrahydrofuran solvent, then cooled to -78 ° C, and a solution of intermediate 1 (22.6 g, 0.1 mol) and 40 mL of tetrahydrofuran was slowly added dropwise. After the addition was complete, the temperature was slowly raised to 0 ° C and the reaction was carried out for 5 hours. Then trifluoromethanesulfonic anhydride (29.6 g, 0.105 mol) was slowly added dropwise. After the addition was complete, the temperature was raised to room temperature and the reaction was carried out for 2 hours. 100 mL of saturated aqueous ammonium chloride solution was added to quench, and then extracted twice with 300 mL of dichloromethane. The organic layers were combined and concentrated. The crude product was purified by column chromatography with an eluent of ethyl acetate / petroleum ether (v / v=1 / 5-20) to obtain the product intermediate 2, 26.9 g, with a yield of 75%, and HPLC 99.1%. 1HNMR(400MHz, CDCl3):8.23(d,1H),8.11(d,1H),8.01(d,1H),7.95(d,1H).

[0035] Example 3

[0036]

[0037] Under argon protection, intermediate 2 (12.3 g, 0.05 mol), cesium fluoride (7.6 g, 0.05 mol) and tetramethylammonium fluoride (9 g, 0.01 mol) were mixed in 150 mL of cyclohexane, heated to 90 ° C, reacted for 6 hours, cooled to room temperature, filtered, concentrated, and the crude product was purified by column chromatography with eluent ethyl acetate / n-hexane (v / v=1 / 2-20) to generate 1-fluoro-2-trifluoromethanesulfonylbenzene, 10.4 g, yield 91%, HPLC 99.2%. 1 HNMR (400MHz, CDCl3): 8.16 (m, 2H), 7.80 (m 1H), 7.69 (m, 1H).

[0038] Example 4

[0039] Under argon protection, intermediate 2 (12.3 g, 0.05 mol) and cesium fluoride (11.4 g, 0.075 mol) were mixed in 150 mL of cyclohexane sulfone, heated to 120 ° C, reacted for 10 hours, cooled to room temperature, filtered, concentrated, and the crude product was purified by column chromatography with ethyl acetate / n-hexane (v / v = 1 / 2-20) as eluent to generate 1-fluoro-2-trifluoromethanesulfonylbenzene, 6.8 g, yield 60%, HPLC 98.5%.

[0040] Example 5

[0041] Under argon protection, intermediate 2 (12.3 g, 0.05 mol) and tetramethylammonium fluoride (11.4 g, 0.075 mol) were mixed in 150 mL of cyclohexane, heated to 100 ° C, reacted for 10 hours, cooled to room temperature, filtered, concentrated, and the crude product was purified by column chromatography with ethyl acetate / n-hexane (v / v=1 / 2-20) as eluent to generate 1-fluoro-2-trifluoromethanesulfonylbenzene, 8.3 g, yield 73%, HPLC 98.8%.

[0042] The above description is only a preferred specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes according to the technical scheme and inventive concept of the present invention within the technical scope disclosed by the present invention, which should be covered by the protection scope of the present invention.

Claims

1. A method for preparing 1-fluoro-2-trifluoromethanesulfonylbenzene, characterized in that: The steps include: A. Phenol and trifluoromethanesulfonic anhydride are mixed in a base to generate intermediate 1; B. Mixing intermediate 1 and LDA in THF, reacting under low temperature conditions, and then reacting with trifluoromethanesulfonic anhydride to generate intermediate 2; C. Mix the intermediate 2 with a fluorination agent in a solvent and react at elevated temperature to generate 1-fluoro-2-trifluoromethanesulfonylbenzene.

2. The method for preparing 1-fluoro-2-trifluoromethanesulfonylbenzene according to claim 1, characterized in that: In step A, the base is selected from diisopropylethylamine or pyridine.

3. The method for preparing 1-fluoro-2-trifluoromethanesulfonylbenzene according to claim 1, characterized in that: In step A, the molar ratio of phenol to trifluoromethanesulfonic anhydride is 1:1-1.

2.

4. The method for preparing 1-fluoro-2-trifluoromethanesulfonylbenzene according to claim 1, characterized in that: In step B, the low temperature condition is -78-0°C.

5. The method for preparing 1-fluoro-2-trifluoromethanesulfonylbenzene according to claim 1, characterized in that: In step B, the molar ratio of the intermediate 1, LDA and trifluoromethanesulfonic anhydride is 1:1-1.1:1-1.

1.

6. The method for preparing 1-fluoro-2-trifluoromethanesulfonylbenzene according to claim 1, characterized in that: In step C, the fluorination agent is selected from one or both of CsF and tetramethylammonium fluoride.

7. The method for preparing 1-fluoro-2-trifluoromethanesulfonylbenzene according to claim 1, characterized in that: In step C, the solvent is sulfolane.

8. The method for preparing 1-fluoro-2-trifluoromethanesulfonylbenzene according to claim 1, characterized in that: In step C, the temperature is raised to 80-120°C.

9. The method for preparing 1-fluoro-2-trifluoromethanesulfonylbenzene according to claim 1, characterized in that: In step C, the molar ratio of the intermediate 2 to the fluorination reagent is 1:1-1.5.

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