4- [ [ (4, 5-dihydro-5, 5-dimethyl-3-isoxazolyl)thio]methyl] -1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-ol synthesis

Abstract

This invention discloses a method for synthesizing a sulfonylpyrazine intermediate. The reaction steps are as follows: 2-methyl-3-butyn-2-ol and p-toluenesulfonyl chloride react in the presence of an acid-binding agent to obtain compound A; compound A reacts with hydroxylamine in the presence of a catalyst to obtain compound B; compound B undergoes cyclization under alkaline conditions to obtain compound C; compound C reacts with elemental sulfur to obtain compound D; and compound D reacts with compound E to generate 4-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)thio]methyl]-1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-ol (sulfonylpyrazine intermediate F). The synthesis method of this invention is characterized by its simple synthesis process, easy product separation, and low equipment requirements. Through optimization of reaction conditions, the product purity and yield are both high, making it suitable for industrial production.

Description

Technical Field

[0001] This invention relates to a method for synthesizing sulfonylpyrazine intermediates, specifically to a simple and easy-to-operate method for synthesizing sulfonylpyrazine intermediate F (4-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)thio]methyl]-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-ol), belonging to the field of organic synthesis technology. Background Technology

[0002] Sulfonazole was developed by Japan Combinatorial Chemicals Co., Ltd., with the chemical name 3-[5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)pyrazol-4-ylmethylsulfonyl]-4,5-dihydro-5,5-dimethyl-1,2-isoxazole, and has the structure shown below:

[0003]

[0004] Sulfonazole can be used as a pre-emergence soil treatment agent in most crop fields. After application, it is absorbed by the young roots and shoots of weeds, inhibiting early seedling growth and destroying meristems and coleoptiles. It is a serious potential inhibitor in the biosynthesis of VLCFA (very long side chain fatty acids) (C20-C30) in plants.

[0005] Sulfonpyrazole 3-[5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)pyrazole-4-ylmethylsulfonyl]-4,5-dihydro-5,5-dimethyl-1,2-isoxazole, has the following prior art reports:

[0006] (1) Patent CN102666503 discloses that it can be synthesized using the following path:

[0007]

[0008] The specific steps include: under alkaline conditions, 1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-ol, an aqueous formaldehyde solution, and 5,5-dimethyl-4,5-dihydroisoxazolethionine hydrochloride undergo a condensation reaction in water, followed by alkylation with Freon to obtain the sulfonylpyrazol intermediate 3-[[5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)pyrazole-4-yl]methylthioalkyl]-5,5-dimethyl-4H-1,2-oxazole, which is then oxidized with hydrogen peroxide to obtain sulfonylpyrazol 3-[5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)pyrazole-4-ylmethylsulfonyl]-4,5-dihydro-5,5-dimethyl-1,2-isoxazole. However, this synthetic method has drawbacks such as low product yield, sulfur-containing wastewater, and difficulty in treating the waste.

[0009] (2) Patent CN101213181A reports a method for synthesizing the key intermediate of sulfonylpyrazine via the following route:

[0010]

[0011] The above method involves a substitution reaction under alkaline conditions, but due to the poor activity of the substrate and the low solubility in the water system, the reaction yield is very low, less than 70%. Summary of the Invention

[0012] To address the shortcomings of existing technologies, this invention provides a method for synthesizing sulfonylpyrazine intermediate F. This method offers a new route for the synthesis of sulfonylpyrazine intermediate F, which has fewer reaction steps, faster reaction speed, simpler synthesis process, easier product separation, less waste generated during the reaction, better environmental performance, and higher purity and yield of the product, making it suitable for industrial applications.

[0013] The structural formula of the sulfonylpyrazol intermediate (4-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)thio]methyl]-1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-ol) provided by this invention is as follows:

[0014] .

[0015] The specific technical solution of this invention is as follows:

[0016] This invention provides a method for synthesizing a sulfonylpyrazole intermediate (4-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)thio]methyl]-1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-ol), wherein the sulfonylpyrazole intermediate F is obtained by reacting 2-methyl-3-butyn-2-ol and p-toluenesulfonyl chloride in the presence of an acid-binding agent to obtain compound A; compound A reacts with hydroxylamine in the presence of a catalyst to obtain compound B; compound B undergoes cyclization under alkaline conditions to obtain compound C; compound C reacts with S8 to obtain compound D; and compound D reacts with compound E to obtain 4-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)thio]methyl]-1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-ol (sulfonylpyrazole intermediate F).

[0017] The specific reaction formula is as follows:

[0018] .

[0019] Furthermore, in the synthesis of compound A, the molar ratio of 2-methyl-3-butyn-2-ol to p-toluenesulfonyl chloride is 1:1.03 to 1.2; the reaction temperature is -5 to 0℃; and the acid-binding agent used is an inorganic or organic acid-binding agent.

[0020] Preferably, the acid-binding agent includes, but is not limited to: sodium carbonate, cesium carbonate, potassium carbonate, and triethylamine.

[0021] The synthesis method provided by this invention involves the reaction of compound A being carried out in a solvent; the solvent includes, but is not limited to, benzene-based solvents and alkane-based solvents; preferably, the solvent is toluene, xylene, or cyclohexane.

[0022] Furthermore, in the synthesis of compound B, the molar ratio of compound A to hydroxylamine is 1:1.03–1.3. The solvents used include, but are not limited to, toluene, dichloromethane, and dichloroethane; the reaction temperature is 40–90°C; the catalyst used is a gold catalyst; preferably, the gold catalyst is Ph3PAuNTf2, Ph3PAuCl, or SPhosAuNTf2; the amount of the catalyst used is 1%–5% of the molar amount of compound A.

[0023] Furthermore, in the synthesis of compound C, the solvents used include, but are not limited to, dichloromethane, dichloroethane, dioxane, DMF, and DMAC; the reaction temperature is 60-100℃; and the bases used are KOH, NaOH, and cesium carbonate.

[0024] Furthermore, in the synthesis of compound D, the molar ratio of compound C to sulfur powder (S) is 1:1.03–2.5. Solvents used include, but are not limited to, DMF and DMAC; the reaction temperature is 60–100 °C.

[0025] Furthermore, in the synthesis of compound F, the molar ratio of compound D to compound E is 1:1.03–1.3. The solvents used include, but are not limited to, DMF, DMAC, and water; the reaction temperature is 0–30°C; during the condensation reaction, after mixing compound D and compound E, a base is added; the base is NaOH or KOH; after the reaction is complete, an acid is added to adjust the pH value; the acid is hydrochloric acid.

[0026] This invention provides a novel method for synthesizing sulfonylpyrazine intermediates, which has the following advantages compared to existing synthesis methods:

[0027] (1) The reaction conditions of this invention are mild, do not require high pressure, and have low requirements for equipment;

[0028] (2) The raw materials of this invention are inexpensive and readily available, and the process is simple to operate;

[0029] (3) The products obtained by this invention are easy to separate, and the post-processing is simple and extensive, making them suitable for large-scale production;

[0030] (4) The three wastes generated during the synthesis process of this invention are small, easy to treat, and environmentally friendly. Attached Figure Description

[0031] Figure 1The image shows the 1H NMR spectrum of the sulfonylpyrazol intermediate F synthesized in Example 1. Detailed Implementation

[0032] The present invention will be further described below with reference to specific embodiments. The following description is merely exemplary and does not limit the scope of protection. Other embodiments obtained by those skilled in the art without creative effort, without departing from the inventive concept of the present invention, are also within the scope of protection.

[0033] Unless otherwise specified, all concentrations mentioned in the following embodiments are mass percentage concentrations.

[0034] In the following examples, yield = actual product mass × purity / theoretical product mass.

[0035] In the following examples, the purity of the raw material 2-methyl-3-butyn-2-ol was 98%, and the purity of the catalyst was 98%.

[0036] Example 1

[0037] Synthesis of Compound A: At room temperature, 10.0 g (0.117 mol) of 2-methyl-3-butyn-2-ol was added to 40.0 g of toluene, stirred, and cooled to approximately -5 °C. 8.1 g (0.0757 mol) of sodium carbonate and 24.3 g of water were added. 23.6 g (0.122 mol) of p-toluenesulfonyl chloride was dissolved in 23.6 g of toluene and placed in a constant-pressure dropping funnel. The addition was controlled at -5 to 0 °C, and the mixture was kept at this temperature for 2 hours after the addition was complete. Central analysis showed that 2-methyl-3-butyn-2-ol was <0.5%, indicating the reaction was complete. The mixture was washed with 60 g of water, and the pH was adjusted to neutral with hydrochloric acid. The layers separated, and the aqueous phase was extracted a second time with 60 g of toluene, resulting in another layer separation. The toluene phases from the two extractions were combined, and after rotary evaporation to remove solvent, 28.0 g of compound A with a purity of 94.60% was obtained.

[0038] Synthesis of compound B: 28.0 g (0.111 mol) of compound A, 60 g of dichloroethane, 4.12 g (0.122 mol) of hydroxylamine, and 1.84 g (0.00244 mol) of catalyst Ph3PAuNTf2 were added sequentially to a four-necked flask. The mixture was stirred and heated to 80 °C for 6 hours. After central control analysis, compound A was found to be less than 0.5% and the reaction was complete. The resulting compound B reaction solution was directly added to the next step of synthesizing compound C without separation.

[0039] Synthesis of compound C: 12.73 g (0.113 mol) of 50% KOH aqueous solution was added dropwise to the reaction solution of compound B. After the addition was complete, the temperature was raised to 60℃ and the reaction was maintained for 22 hours. After analysis, compound B was found to be <0.5% indicating the reaction was complete. 30 g of water was added for washing, and the pH was adjusted to neutral with hydrochloric acid. The phases separated, and the aqueous phase was extracted a second time with 30 g of dichloroethane, resulting in another separation. The dichloroethane phases from the two extractions were combined, and after rotary evaporation to remove solvent, 8.32 g of compound C with a purity of 90.0% was obtained.

[0040] Synthesis of compound D: Compound C 8.32 g (0.0755 mol), DMF solvent 80 g, and sulfur powder 4.95 g (0.151 mol) were added sequentially to a four-necked flask. The mixture was heated to 100 °C and stirred for 3 hours. After monitoring, compound C was found to be less than 0.5% and the reaction was complete. The mixture was then filtered to obtain the reaction solution of compound D.

[0041] Synthesis of compound E: 34.2 g of 1-methyl-3-trifluoromethyl-5-hydroxy-1H-pyrazole (0.2 mol, 97%, 1.0 eq), 200 ml of ethanol, and 80.0 g of sodium hydroxide solution (0.6 mol, 30%, 3.0 eq) were added dropwise at a controlled temperature of 15 °C. After the addition was completed in about 0.5 h, the reaction was continued at 10–15 °C for about 5 h. After the reaction was completed, the 1-methyl-3-trifluoromethyl-5-hydroxy-1H-pyrazole content was <0.5%, and the alkaline aqueous solution of compound E was obtained.

[0042] Synthesis of compound F: 33.07 g (0.067 mol) of an alkaline aqueous solution of compound E was added dropwise to the reaction solution of compound D. After the addition was complete, 12.85 g (0.128 mol) of a 40% sodium hydroxide solution was added dropwise. After the addition was complete, the reaction was maintained at 20-30℃ for 3 hours. Central control analysis showed that compound D < 0.5%, indicating the reaction was complete. The pH was adjusted to 2-3 with hydrochloric acid, and the mixture was cooled to 0℃ to precipitate a solid. The solid was filtered, and the filter cake was washed with 30 g of water and dried to obtain 20.98 g of a white solid, which was compound F. The purity was determined to be 90.0%, and the yield (based on 2-methyl-3-butyn-2-ol) was 52.4% over five steps.

[0043] The structural formula of the synthesized product 4-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)thio]methyl]-1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-ol is as follows:

[0044]

[0045] Example 2

[0046] Compound F was prepared according to the method of Example 1, except that the acid-binding agent was changed from sodium carbonate to triethylamine during the synthesis of compound A. See below:

[0047] Synthesis of Compound A: At room temperature, 10.0 g (0.117 mol) of 2-methyl-3-butyn-2-ol was added to 40.0 g of toluene, stirred, and cooled to approximately -5 °C. Then, 15.48 g (0.151 mol) of triethylamine and 24.3 g of water were added. 23.6 g (0.122 mol) of p-toluenesulfonyl chloride was dissolved in 23.6 g of toluene and placed in a constant-pressure dropping funnel. The addition was controlled at -5 to 0 °C, and the mixture was kept at this temperature for 2 hours after the addition was complete. Central analysis showed that 2-methyl-3-butyn-2-ol was <0.5%, indicating the reaction was complete. The mixture was washed with 60 g of water, and the pH was adjusted to neutral with hydrochloric acid. The layers separated, and the aqueous phase was extracted a second time with 60 g of toluene, resulting in another layer separation. The toluene phases from the two extractions were combined, and after rotary evaporation to remove solvent, 26.0 g of compound A with a purity of 94.80% was obtained.

[0048] Synthesis of compound B: 26.0 g (0.103 mol) of compound A, 60 g of dichloroethane, 3.83 g (0.114 mol) of hydroxylamine, and 21.72 g (0.00228 mol) of catalyst Ph3PAuNTf were added sequentially to a four-necked flask. The mixture was stirred and heated to 80 °C for 6 hours. After central control analysis, compound A was found to be less than 0.5% of the total. The reaction was considered complete. The resulting compound B reaction solution was directly added to the next step of synthesizing compound C without separation.

[0049] Synthesis of compound C: 11.84 g (0.105 mol) of 50% KOH aqueous solution was added dropwise to the reaction solution of compound B. After the addition was complete, the temperature was raised to 60℃ and the reaction was maintained for 22 hours. After analysis, compound B was found to be <0.5%, indicating the reaction was complete. 30 g of water was added for washing, and the pH was adjusted to neutral with hydrochloric acid. The phases separated, and the aqueous phase was extracted a second time with 30 g of dichloroethane, resulting in another separation. The dichloroethane phases from the two extractions were combined, and after rotary evaporation to remove solvent, 7.75 g of compound C with a purity of 90.0% was obtained.

[0050] Synthesis of compound D: 7.75 g (0.0703 mol) of compound C, 80 g of DMF solvent, and 4.60 g (0.141 mol) of sulfur powder were added sequentially to a four-necked flask. The mixture was heated to 100 °C and stirred for 3 hours. After monitoring, compound C was found to be less than 0.5% and the reaction was considered complete. The mixture was then filtered to obtain the reaction solution of compound D.

[0051] Synthesis of compound F: 30.78 g (0.063 mol) of an alkaline aqueous solution of compound E was added dropwise to the reaction solution of compound D. After the addition was complete, 11.95 g (0.119 mol) of a 40% sodium hydroxide solution was added dropwise. After the addition was complete, the reaction was maintained at 20-30℃ for 3 hours. Central control analysis showed that compound D < 0.5%, indicating the reaction was complete. The pH was adjusted to 2-3 with hydrochloric acid, and the mixture was cooled to 0℃ to precipitate a solid. The solid was filtered, and the filter cake was washed with 30 g of water and dried to obtain 19.52 g of a white solid, which was compound F. The purity was determined to be 90.0%, and the yield (based on 2-methyl-3-butyn-2-ol) was 48.75% over five steps.

[0052] Example 3

[0053] Compound F was prepared according to the method of Example 1, except that the catalyst for the synthesis of compound B was changed from Ph3PAuNTf2 to Ph3PAuCl. See below:

[0054] Synthesized compound A: See Example 1.

[0055] Synthesis of compound B: 28.0 g (0.111 mol) of compound A, 60 g of dichloroethane, 4.12 g (0.122 mol) of hydroxylamine, and 1.23 g (0.00244 mol) of catalyst Ph3PAuCl were added sequentially to a four-necked flask. The mixture was stirred and heated to 80 °C for 6 hours. After central control analysis, compound A was found to be less than 0.5% and the reaction was complete. The resulting compound B reaction solution was directly added to the next step of synthesizing compound C without separation.

[0056] Synthesis of compound C: 11.97 g (0.107 mol) of 50% KOH aqueous solution was added dropwise to the reaction solution of compound B. After the addition was complete, the temperature was raised to 60℃ and the reaction was maintained for 22 hours. After analysis, compound B was found to be <0.5% indicating the reaction was complete. 30 g of water was added for washing, and the pH was adjusted to neutral with hydrochloric acid. The phases separated, and the aqueous phase was extracted a second time with 30 g of dichloroethane, resulting in another separation. The dichloroethane phases from the two extractions were combined, and after rotary evaporation to remove solvent, 7.83 g of compound C with a purity of 90.0% was obtained.

[0057] Synthesis of compound D: 7.83 g (0.0711 mol) of compound C, 80 g of DMF solvent, and 4.65 g (0.142 mol) of sulfur powder were added sequentially to a four-necked flask. The mixture was heated to 100 °C and stirred for 3 hours. After monitoring, compound C was found to be less than 0.5% and the reaction was considered complete. The mixture was then filtered to obtain the reaction solution of compound D.

[0058] Synthesis of compound F: 31.13 g (0.063 mol) of an alkaline aqueous solution of compound E was added dropwise to the reaction solution of compound D. After the addition was complete, 12.09 g (0.121 mol) of a 40% sodium hydroxide solution was added dropwise. After the addition was complete, the reaction was maintained at 20-30℃ for 3 hours. Central control analysis showed that compound D < 0.5%, indicating the reaction was complete. The pH was adjusted to approximately 2-3 with hydrochloric acid, and the mixture was cooled to 0℃ to precipitate a solid. The solid was filtered, and the filter cake was washed with 30 g of water and dried to obtain 19.74 g of a white solid, which was compound F. The purity was determined to be 90.0%, and the yield (based on 2-methyl-3-butyn-2-ol) was 49.31% over five steps.

[0059] Example 4

[0060] Compound F was prepared according to the method in Example 1, except that the base was changed from KOH to NaOH during the synthesis of compound C. See below:

[0061] Synthesized compound A: See Example 1.

[0062] Synthesized compound B: See Example 1.

[0063] Synthesis of compound C: 9.07 g (0.113 mol) of 50% NaOH aqueous solution was added dropwise to the reaction solution of compound B. After the addition was complete, the temperature was raised to 60℃ and the reaction was maintained for 22 hours. After analysis, compound B was found to be <0.5% indicating the reaction was complete. 30 g of water was added for washing, and the pH was adjusted to neutral with hydrochloric acid. The phases separated, and the aqueous phase was extracted a second time with 30 g of dichloroethane, resulting in another separation. The dichloroethane phases from the two extractions were combined, and after rotary evaporation to remove solvent, 8.12 g of compound C with a purity of 90.0% was obtained.

[0064] Synthesis of compound D: Compound C 8.12 g (0.0737 mol), DMF solvent 80 g, and sulfur powder 4.82 g (0.147 mol) were added sequentially to a four-necked flask. The mixture was heated to 100 °C and stirred for 3 hours. After monitoring, compound C was found to be less than 0.5% and the reaction was complete. The mixture was then filtered to obtain the reaction solution of compound D.

[0065] Synthesis of compound F: 32.25 g (0.066 mol) of an alkaline aqueous solution of compound E was added dropwise to the reaction solution of compound D. After the addition was complete, 12.53 g (0.125 mol) of a 40% sodium hydroxide solution was added dropwise. After the addition was complete, the reaction was maintained at 20-30℃ for 3 hours. Central control analysis showed that compound D < 0.5%, indicating the reaction was complete. The pH was adjusted to approximately 2-3 with hydrochloric acid, and the mixture was cooled to 0℃ to precipitate a solid. The solid was filtered, and the filter cake was washed with 30 g of water and dried to obtain 20.45 g of a white solid, which was compound F. The purity was determined to be 90.0%, and the yield (based on 2-methyl-3-butyn-2-ol) was 51.08% over 5 steps.

[0066] Example 5

[0067] Compound F was prepared according to the method of Example 1, except that the temperature was changed from 100°C to 60°C during the synthesis of compound D. See below:

[0068] Synthesized compound A: See Example 1.

[0069] Synthesized compound B: See Example 1.

[0070] Synthesized compound C: See Example 1.

[0071] Synthesis of compound D: Compound C 8.32 g (0.0755 mol), DMF solvent 80 g, and sulfur powder 4.95 g (0.151 mol) were added sequentially to a four-necked flask. The mixture was heated to 60 °C and stirred for 3 hours. After monitoring, compound C was found to be less than 0.5% and the reaction was considered complete. The mixture was then filtered to obtain the reaction solution of compound D.

[0072] Synthesis of compound F: 31.13 g (0.063 mol) of an alkaline aqueous solution of compound E was added dropwise to the reaction solution of compound D. After the addition was complete, 12.09 g (0.121 mol) of a 40% sodium hydroxide solution was added dropwise. After the addition was complete, the reaction was maintained at 20-30℃ for 3 hours. Central control analysis showed that compound D < 0.5%, indicating the reaction was complete. The pH was adjusted to approximately 2-3 with hydrochloric acid, and the mixture was cooled to 0℃ to precipitate a solid. The solid was filtered, and the filter cake was washed with 30 g of water and dried to obtain 19.74 g of a white solid, which was compound F. The purity was determined to be 90.0%, and the yield (based on 2-methyl-3-butyn-2-ol) was 49.30% over five steps.

[0073] Example 6

[0074] Compound F was prepared according to the method of Example 1, except that the base was changed from sodium hydroxide solution to potassium hydroxide solution during the synthesis of compound F. See below:

[0075] Synthesized compound A: See Example 1.

[0076] Synthesized compound B: See Example 1.

[0077] Synthesized compound C: See Example 1.

[0078] Synthesized compound D: See Example 1.

[0079] Synthesis of compound F: 33.07 g (0.067 mol) of an alkaline aqueous solution of compound E was added dropwise to the reaction solution of compound D. After the addition was complete, 18.02 g (0.128 mol) of a 40% potassium hydroxide solution was added dropwise. After the addition was complete, the reaction was maintained at 20-30℃ for 3 hours. Central control analysis showed that compound D < 0.5%, indicating the reaction was complete. The pH was adjusted to approximately 2-3 with hydrochloric acid, and the mixture was cooled to 0℃ to precipitate a solid. The solid was filtered, and the filter cake was washed with 30 g of water and dried to obtain 21.19 g of a white solid, which was compound F. The purity was determined to be 90.0%, and the yield (based on 2-methyl-3-butyn-2-ol) was 52.94% over the five steps.

Claims

1. A method of synthesizing an intermediate of pyroxasulfone, characterized by, Includes the following steps: (A) Condensation reaction: Compound A is obtained by reacting 2-methyl-3-butyn-2-ol and p-toluenesulfonyl chloride in the presence of an acid-binding agent; ； (B) Addition reaction: Compound A reacts with hydroxylamine in the presence of a catalyst to yield compound B; ； The catalyst is a gold catalyst; (C) Ring closure reaction: Compound B undergoes ring closure under basic conditions to yield compound C; ； (D) Sulfidation reaction: Compound C reacts with S8 to give compound D; ； (E) Condensation reaction: Compound D reacts with compound E to generate 4-((5,5-dimethyl-4,5-dihydroisoxazol-3-yl)thio)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-ol, i.e. sulfonylpyrazol intermediate F; In step (E), the reaction temperature is 0-30℃.

2. The method of synthesis of claim 1, wherein, In step (A), the molar ratio of 2-methyl-3-butyn-2-ol to p-toluenesulfonyl chloride is 1:1.03 to 1.2; the acid-binding agent is an inorganic or organic acid-binding agent; the reaction temperature is -5 to 0℃.

3. The method of synthesis of claim 2, wherein, The acid-binding agent is sodium carbonate, cesium carbonate, potassium carbonate, or triethylamine.

4. The method of synthesis according to any one of claims 1 to 3, wherein, In step (A), the condensation reaction is carried out in a solvent; the solvent is a benzene-based solvent or an alkane-based solvent.

5. The method of synthesis of claim 4, wherein, In step (A), the solvent is toluene, xylene, or cyclohexane.

6. The synthesis method according to claim 1, characterized in that, In step (B), the molar ratio of compound A to hydroxylamine is 1:1.03 to 1.3; the gold catalyst is one or more of Ph3PAuNTf2, Ph3PAuCl, or SPhosAuNTf2; the amount of catalyst used is 1% to 5% of the molar amount of compound A; and the reaction temperature is 40-90℃.

7. The synthesis method according to claim 1 or 6, characterized in that, In step (B), the addition reaction is carried out in a solvent; the solvent is toluene, dichloromethane or dichloroethane.

8. The synthesis method according to claim 1, characterized in that, In step (C), the cyclization reaction is carried out in a solvent; the solvent is dichloromethane, dichloroethane, dioxane, DMF or DMAC; the base used is KOH, NaOH or cesium carbonate; the reaction temperature is 60-100℃.

9. The synthesis method according to claim 1, characterized in that, In step (D), the molar ratio of compound C to S8 is 1:1.03 to 2.

5.

10. The synthesis method according to claim 1 or 9, characterized in that, In step (D), the sulfidation reaction is carried out in a solvent; the solvent is DMF or DMAC.

11. The synthesis method according to claim 1, characterized in that, In step (E), the molar ratio of compound D to compound E is 1:1.03 to 1.3; during the condensation reaction, after compound D and compound E are mixed, a base is added; the base is NaOH or KOH; after the reaction is completed, an acid is added to adjust the pH value; the acid is hydrochloric acid.

12. The synthesis method according to claim 1 or 11, characterized in that, In step (E), the condensation reaction is carried out in a solvent; the solvent is DMF, DMAC or water.

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