A process for the preparation of the parasiticides ebsulfur

Abstract

The present application relates to the technical field of organic synthesis, and particularly relates to a method for preparing a parasitic worm inhibitor Ebsulfur. The conventional method for synthesizing Ebsulfur has the problems of complex reaction process, cumbersome steps, relatively harsh reaction conditions and operation, the need to use a transition metal catalyst and poor yield. In view of the above problems, the present application provides a method for preparing a parasitic worm inhibitor Ebsulfur, which uses 3H-1,2-benzene dithiol-3-ketone and aniline as reaction raw materials, uses triphenylphosphine as a key additive, uses trifluorotoluene as a reaction solvent, and is heated and stirred at a temperature of not less than 100 DEG C in a sealed state to obtain Ebsulfur in one step. The method overcomes the defects of the prior art, such as a complex process, the need to use a transition metal catalyst, harsh operation or a low yield.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and specifically to a method for preparing the parasite inhibitor Ebsulfur. Background Technology

[0002] 2-Phenyl-1,2-benzisothiazol-3-one (Ebsulfur), as an antiparasitic molecule of the benzisothiazolone class, specifically targets the key functional enzyme of Trypanosoma brevicornuate, namely trypanosoma thionyl reductase (TryR). This compound exhibits significant inhibitory activity against Trypanosoma brevicornuate, with an IC50 value of [missing information]. 50 Between 61 and 293 nM, it can provide an important research vehicle for studying the mechanism of African trypanosomiasis and developing candidate drugs.

[0003] Currently, there are three main methods for synthesizing Ebsulfur in the literature: (1) Starting with 2-thio-N-phenylbenzamide, Ebsulfur can be constructed in one step by adding NCS, Selectflour, or transition metal catalyst with a high yield. However, the disadvantage of this method is that the raw material 2-thio-N-phenylbenzamide needs to be prepared in advance, and the reaction process is complicated and the steps are cumbersome.

[0004] .

[0005] (2) The target product can be prepared in the presence of a copper salt catalyst using 2-iodo-N-phenylbenzamide and different sulfur sources (elemental sulfur or carbon disulfide) as raw materials, or using benzisothiazolin-3-one and iodobenzene as raw materials, with a yield range of 33% to 63%. The reaction conditions and operation of this method are relatively harsh and complex, and a transition metal catalyst is required.

[0006] .

[0007] (3) Using 2-mercaptobenzoic acid and aniline as raw materials and phosphorus trichloride or phosphorus oxychloride as additives, Ebsulfur is synthesized through multiple steps. The yield of this reaction is much lower than that of conventional synthesis methods, only 22%~31%, with poor raw material utilization and high cost.

[0008] . Summary of the Invention

[0009] The existing technology has the following problems: conventional methods for synthesizing Ebsulfur involve complex and cumbersome processes, relatively harsh reaction conditions and operations, require transition metal catalysts, and have poor yields. To address these problems, this invention provides a method for preparing the parasite inhibitor Ebsulfur. This method involves adding 3H-1,2-benzodithiol-3-one, aniline, and triphenylphosphine to a sealed tube containing an organic solvent, and then heating and stirring the mixture at a temperature not lower than 100°C. After the reaction is complete, the reaction solution is separated and purified to obtain Ebsulfur.

[0010] Preferably, the ratio of 3H-1,2-benzodithiol-3-one, aniline, triphenylphosphine, and organic solvent is 0.2:0.6:(0.2-0.4):(1-3)mL.

[0011] Preferably, the ratio of 3H-1,2-benzodithiol-3-one, aniline, triphenylphosphine, and organic solvent is 0.2:0.6:0.2:2 mL.

[0012] Preferably, the reaction temperature is 100-120℃.

[0013] Preferably, the reaction temperature is 100°C.

[0014] Preferably, the organic solvent is trifluorotoluene.

[0015] Preferably, the separation and purification method involves sequential concentration and silica gel column chromatography purification.

[0016] Preferably, the reaction time is 24-36 hours.

[0017] Preferably, the reaction time is 24 hours.

[0018] Beneficial effects: (1) This invention uses 3H-1,2-benzodithiol-3-one, aniline and triphenylphosphine as raw materials to directly obtain the target product Ebsulfur through a one-step sealed heating reaction in an organic solvent. There is no need to prepare complex intermediates (such as 2-thio-N-phenylbenzamide) in advance, avoiding the cumbersome process of multiple steps and significantly simplifying the synthesis process.

[0019] (2) Existing methods often rely on transition metal catalysts such as copper salts, which not only impose harsh reaction conditions but also introduce metal residues, increasing the difficulty of purification and the risk of environmental pollution. This invention uses triphenylphosphine as an organic promoter, completely avoiding the use of metal catalysts, resulting in cleaner products and simpler post-processing, which is in line with the concept of green chemistry.

[0020] (3) This invention does not use irritating or corrosive reagents such as phosphorus trichloride and phosphorus oxychloride, making the reaction system safer, more friendly to equipment and operators, and reducing production costs and safety hazards.

[0021] (4) The reaction of this invention is carried out in a sealed tube at 100-120℃, which is a moderate temperature range and does not require special high pressure or strong oxidation / reduction conditions. The organic solvent used, trifluorotoluene, is chemically stable and has a suitable boiling point, making it easy to control the reaction process. After the reaction is completed, only concentration and silica gel column chromatography are required to obtain the product, and the post-processing steps are simple and easy to perform.

[0022] (5) The raw materials used in this invention, 3H-1,2-benzodithiol-3-one, aniline and triphenylphosphine, are all commercially available chemicals that do not require special preparation. Moreover, the feeding ratio has been optimized (e.g. 0.2:0.6:0.2:2 mL), which has good atom economy and helps to reduce synthesis costs. It is suitable for laboratory research and industrial production.

[0023] In summary, this invention overcomes the shortcomings of existing technologies, such as complex processes, the need for transition metal catalysts, harsh operations, or low yields, and provides a new method for preparing Ebsulfur that is simple, safe, environmentally friendly, and easy to implement. Detailed Implementation

[0024] The present invention will be described in detail below with reference to embodiments. However, it should be understood that the following embodiments are merely illustrative examples of implementation of the present invention and are not intended to limit the scope of the present invention.

[0025] Example 1 3H-1,2-benzodithiol-3-one (0.2 mmol), aniline (0.6 mmol), triphenylphosphine (0.2 mmol), and trifluorotoluene (2 mL) were added sequentially to a 25 mL sealed tube. The mixture was stirred vigorously at 100 °C for 24 hours. After the reaction was completed, the reaction solution was concentrated and separated by column chromatography to obtain 31.8 mg of Ebsulfur, with a yield of 70%.

[0026] .

[0027] NMR and mass spectrometry data of the target product: 1 H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 7.9 Hz,1H), 7.63 – 7.61 (m, 2H), 7.58 – 7.54 (m, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.39– 7.32 (m, 3H), 7.22 (t,J = 7.4 Hz, 1H). 13 120.14 MS (EI) = 227 [M + ] Solvent selection Comparative Example 1 is the same as Example 1, except that the reaction solvent used in Comparative Example 1 is toluene.

[0028] Comparative Example 2 is the same as Example 1, except that the reaction solvent used in Comparative Example 2 is fluorobenzene.

[0029] Comparative Example 3 is the same as Example 1, except that the reaction solvent used in Comparative Example 3 is dichloromethane.

[0030] Comparative Example 4 is the same as Example 1, except that the reaction solvent used in Comparative Example 4 is tetrahydrofuran.

[0031] Comparative Example 5 is the same as Example 1, except that the reaction solvent used in Comparative Example 5 is anhydrous methanol.

[0032] Comparative Example 6 is the same as Example 1, except that the reaction solvent used in Comparative Example 6 is anhydrous ethanol.

[0033] Comparative Example 7 is the same as Example 1, except that the reaction solvent used in Comparative Example 7 is N,N-dimethylformamide.

[0034] Comparative Example 8 is the same as Example 1, except that the reaction solvent used in Comparative Example 8 is dimethyl sulfoxide.

[0035] Comparative Example 9 is the same as Example 1, except that the reaction solvent used in Comparative Example 9 is acetonitrile.

[0036] Comparative Example 10 is the same as Example 1, except that the reaction solvent used in Comparative Example 10 is ethyl acetate.

[0037] Screening of triphenylphosphine dosage Example 2 is the same as Example 1, except that the amount of triphenylphosphine used in Example 2 is 0.4 mmol.

[0038] Comparative Example 11 is the same as Example 1, except that the amount of triphenylphosphine used in Comparative Example 11 is 0.6 mmol.

[0039] Screening of reaction time Example 3 is the same as Example 1, except that the reaction time in Example 3 is 36 hours.

[0040] Comparative Example 12 is the same as Example 1, except that the reaction time in Comparative Example 12 is 12 hours.

[0041] Screening of reaction temperature Example 4 is the same as Example 1, except that the reaction temperature in Example 4 is 120°C.

[0042] Comparative Example 13 is the same as Example 1, except that the reaction temperature in Comparative Example 13 is 80°C.

[0043] Screening of trifluorotoluene dosage Example 5 is the same as Example 1, except that the amount of trifluorotoluene used in Example 5 is 1 mL.

[0044] Example 6 is the same as Example 1, except that the amount of trifluorotoluene used in Example 6 is 3 mL.

[0045] The yields of the target product Ebsulfur in the embodiments and comparative examples of the present invention were tested, calculated, and compared. The comparison results are shown in Tables 1 and 2. The formula for calculating the yield is: Yield (%) = (Actual mass of Ebsulfur / Theoretical mass of Ebsulfur) × 100%.

[0046] Table 1 Table 2 Based on the above-described preferred embodiments of the present invention, and through the foregoing description, those skilled in the art can make various changes and modifications without departing from the inventive concept. The technical scope of this invention is not limited to the contents of the specification, but must be determined according to the scope of the claims.

Claims

1. A method for preparing the parasite inhibitor Ebsulfur, characterized in that, 3H-1,2-benzodithiol-3-one, aniline, and triphenylphosphine were added to a sealed tube containing an organic solvent. The tube was then heated and stirred at a temperature not lower than 100°C. After the reaction was completed, the reaction solution was separated and purified to obtain Ebsulfur.

2. The method for preparing the parasite inhibitor Ebsulfur according to claim 1, characterized in that, The ratio of 3H-1,2-benzodithiol-3-one, aniline, triphenylphosphine, and organic solvent is 0.2:0.6:(0.2-0.4):(1-3)mL.

3. The method for preparing the parasite inhibitor Ebsulfur according to claim 1, characterized in that, The ratio of 3H-1,2-benzodithiol-3-one, aniline, triphenylphosphine, and organic solvent used is 0.2:0.6:0.2:2 mL.

4. The method for preparing the parasite inhibitor Ebsulfur according to claim 1, characterized in that, The reaction temperature is 100-120℃.

5. The method for preparing the parasite inhibitor Ebsulfur according to claim 1, characterized in that, The reaction temperature is 100℃.

6. The method for preparing the parasite inhibitor Ebsulfur according to claim 1, characterized in that, The organic solvent is trifluorotoluene.

7. The method for preparing the parasite inhibitor Ebsulfur according to claim 1, characterized in that, The separation and purification method involves sequential concentration and silica gel column chromatography purification.

8. The method for preparing the parasite inhibitor Ebsulfur according to claim 1, characterized in that, The reaction time is 24-36 hours.

9. The method for preparing the parasite inhibitor Ebsulfur according to claim 1, characterized in that, The reaction time is 24 hours.

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