Synthesis method of 3-phenyl-5-(thiophene-2-yl)-1, 2, 4-oxadiazole
By using benitrile and 2-thiophene formic acid as raw materials, combined with addition reaction, acylation reaction and cyclization reaction, and combined with recrystallization technology, the problem of low synthesis yield of 3-phenyl-5-(thiophene-2-yl)-1,2,4-oxadiazole was solved, and an efficient product yield was achieved, reaching more than 85%.
Patent Information
- Application Number
- CN202411762032.5
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-12-03
- Publication Date
- 2025-02-25
AI Technical Summary
In the prior art, the synthesis yield of 3-phenyl-5-(thiophene-2-yl)-1,2,4-oxadiazole is relatively low and it is difficult to meet the needs of industrial production.
Benzonitrile and 2-thiophene formic acid are used as raw materials, and 3-phenyl-5-(thiophene-2-yl)-1,2,4-oxadiazole is prepared by addition reaction, acylation reaction and cyclization reaction, combined with recrystallization technology. The specific steps include: using hydroxylamine hydrochloride and benzonitrile in S1 to perform addition reaction under the action of an alkaline acid binding agent to obtain N-hydroxybenzamidine; using 2-thiophene formic acid in S2 to perform acylation reaction under the action of sulfoxide chloride and catalyst to obtain 2-thiophene formyl chloride; in S3, N-hydroxybenzamidine and 2-thiophene formyl chloride are cyclized under the action of alkaline substances, and the target product is obtained after crystallization and recrystallization.
Through this method, the yield of 3-phenyl-5-(thiophene-2-yl)-1,2,4-oxadiazole is increased, reaching more than 85%, meeting the demand for industrial production.
Abstract
Description
Technical Field
[0001] The invention relates to the technical field of pesticide synthesis, and in particular to a method for synthesizing 3-phenyl-5-(thiophene-2-yl)-1,2,4-oxadiazole. Background Art
[0002] 3-phenyl-5-(thiophene-2-yl)-1,2,4-oxadiazole is a new type of oxadiazole nematicide, also known as Tioxazafen, which is mainly used for soil pest and nematode treatment. It has broad-spectrum nematicidal activity against cyst nematodes and root-knot nematodes in plants such as corn, soybeans, and cotton. At present, the harm caused by nematodes is becoming more and more serious, posing a serious threat to crop production. Parasitic nematodes damage plant roots, and after infection, they are prone to pathogenic fungal infection, aggravating the damage of bacteria, fungi and viruses, destroying plant growth, and reducing crop yield and quality. The launch of 3-phenyl-5-(thiophen-2-yl)-1,2,4-oxadiazole has added a powerful tool for the prevention and control of nematodes. However, there are currently few reports on 3-phenyl-5-(thiophen-2-yl)-1,2,4-oxadiazole and the yield is low. Therefore, the development of a high-yield synthesis method for 3-phenyl-5-(thiophen-2-yl)-1,2,4-oxadiazole is a problem that needs to be solved. Summary of the invention
[0003] The invention provides a method for synthesizing 3-phenyl-5-(thiophene-2-yl)-1,2,4-oxadiazole, which solves the problem of low synthesis yield of 3-phenyl-5-(thiophene-2-yl)-1,2,4-oxadiazole in the related art.
[0004] The technical solution of the present invention is as follows: The present invention provides a method for synthesizing 3-phenyl-5-(thiophene-2-yl)-1,2,4-oxadiazole, comprising the following steps: S1, using benzonitrile as a raw material, adding hydroxylamine hydrochloride, under the action of an alkaline acid binding agent, undergoing addition reaction, crystallization, and recrystallization to obtain N-hydroxybenzamidine; S2, using 2-thiophenecarboxylic acid as a raw material, under the action of thionyl chloride and a catalyst, undergoing acylation reaction and distillation to obtain 2-thiophenecarboxylic acid chloride; S3, subjecting N-hydroxybenzamidine and 2-thiophenecarbonyl chloride to a basic substance, subjecting them to a cyclization reaction, crystallization, and recrystallization to obtain 3-phenyl-5-(thiophene-2-yl)-1,2,4-oxadiazole; The solvents for recrystallization in step S1 and step S3 independently include one or more of n-hexane, chloroform and dimethyl carbonate.
[0005] As a further technical solution, in steps S1 and S3, the recrystallization solvents independently include n-hexane and dimethyl carbonate.
[0006] In the present invention, the yield of 3-phenyl-5-(thiophen-2-yl)-1,2,4-oxadiazole is further improved by limiting the solvent for recrystallization to consist of n-hexane and dimethyl carbonate.
[0007] As a further technical solution, in step S1, the volume ratio of n-hexane to dimethyl carbonate is 4-8:1.
[0008] In the present invention, by limiting the volume ratio of n-hexane and dimethyl carbonate in the recrystallization solvent in step S1 to 4-8:1, the yield of 3-phenyl-5-(thiophen-2-yl)-1,2,4-oxadiazole is further improved.
[0009] As a further technical solution, in step S3, the volume ratio of n-hexane to dimethyl carbonate is 1:5-10.
[0010] In the present invention, by limiting the volume ratio of n-hexane and dimethyl carbonate in the recrystallization solvent in step S3 to 1:5-10, the yield of 3-phenyl-5-(thiophen-2-yl)-1,2,4-oxadiazole is further improved.
[0011] As a further technical solution, the alkaline acid binding agent includes one or more of sodium carbonate, potassium carbonate, and cesium carbonate.
[0012] As a further technical solution, the molar ratio of the benzonitrile, hydroxylamine hydrochloride and alkaline acid binding agent is 1:2:1.1~1.3.
[0013] As a further technical solution, the catalyst is N,N-dimethylformamide; the molar ratio of the 2-thiophenecarboxylic acid to the catalyst is 1:0.1-0.2; and the mass ratio of the 2-thiophenecarboxylic acid to thionyl chloride is 1:4-5.
[0014] As a further technical solution, the solvent for the addition reaction includes one or more of methanol, ethanol, isopropanol, and ethyl acetate; the solvent for the acylation reaction includes one or two of dichloromethane and chloroform; and the solvent for the cyclization reaction includes one or more of butyl acetate, toluene, and methyl butyl ketone.
[0015] As a further technical solution, the alkaline substance includes one or more of lithium hydroxide, sodium hydroxide, and potassium hydroxide; the molar ratio of N-hydroxybenzamidine, 2-thenoyl chloride, and the alkaline substance is 1:1.1:2~3.
[0016] As a further technical solution, at least one of the following features is included: The temperature of the addition reaction is 40-50°C, and the time of the addition reaction is 6-7h; The temperature of the acylation reaction is 25-35°C, and the time of the acylation reaction is 10-15h; The temperature of the cyclization reaction is 80-100°C, and the time of the cyclization reaction is 6-7h; The distillation temperature is 60-65°C; The crystallization temperature in step S1 and step S3 is independently -5 to 5°C, and the crystallization time is independently 1 to 2 hours; The recrystallization temperatures in step S1 and step S3 are independently 50-70° C., and the recrystallization times are independently 2-3 hours.
[0017] The working principle and beneficial effects of the present invention are: In the present invention, benzonitrile and 2-thiophenecarboxylic acid are used as starting materials, and 3-phenyl-5-(thiophene-2-yl)-1,2,4-oxadiazole is obtained through addition reaction, acylation reaction and cyclization reaction. In the present invention, the raw materials are easily available and the reaction conditions are mild. The yield of the product is improved by adopting a recrystallization method, so that the yield of 3-phenyl-5-(thiophene-2-yl)-1,2,4-oxadiazole can reach more than 85%. DETAILED DESCRIPTION
[0018] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.
[0019] Example 1 A method for synthesizing 3-phenyl-5-(thiophene-2-yl)-1,2,4-oxadiazole comprises the following steps: S1. Add 69.5 g of hydroxylamine hydrochloride to 150 mL of ethanol, add 58.3 g of sodium carbonate and 51.5 g of benzonitrile, heat to 40 ° C for 7 hours, and after the reaction is completed, cool the reaction to -5 ° C for crystallization for 1 hour. After filtering out the solid, add it to 250 mL of a mixed solution of n-hexane and chloroform (the volume ratio of n-hexane to chloroform is 1:1), recrystallize at 50 ° C for 3 hours, filter out the solid, and dry it to obtain 61.6 g of N-hydroxybenzamidine; S2, add 128g of 2-thiophenecarboxylic acid to 400mL of dichloromethane solution, add 7.3g of N,N-dimethylformamide, and then add 512g of thionyl chloride, react at 25°C for 15h, and collect the fraction at 65°C by reduced pressure distillation to obtain 131.7g of 2-thiophenecarboxylic acid chloride; S3. Add 61.6 g of N-hydroxybenzamidine to 300 mL of butyl acetate, add 36.2 g of sodium hydroxide and 73.0 g of 2-thiophenecarbonyl chloride in sequence, heat to 80 ° C for reaction for 7 h, cool to -5 ° C for crystallization for 1 h, filter out the solid, add to 200 mL of a mixed solution of n-hexane and chloroform (the volume ratio of n-hexane to chloroform is 1:1), recrystallize at 50 ° C for 3 h, filter, and dry to obtain 99.2 g of 3-phenyl-5-(thiophene-2-yl)-1,2,4-oxadiazole with a purity of 98.5% and a yield of 85.7%.
[0020] Example 2 A method for synthesizing 3-phenyl-5-(thiophene-2-yl)-1,2,4-oxadiazole comprises the following steps: S1. Add 69.5 g of hydroxylamine hydrochloride to 150 mL of methanol, add 89.7 g of potassium carbonate and 51.5 g of benzonitrile, heat to 50 ° C for 6 hours, and after the reaction is completed, cool the reaction to 5 ° C for crystallization for 2 hours. After filtering out the solid, add it to 250 mL of a mixed solution of n-hexane and chloroform (the volume ratio of n-hexane to chloroform is 1:1), recrystallize at 70 ° C for 2 hours, filter out the solid, and dry it to obtain 62.0 g of N-hydroxybenzamidine; S2, add 128g of 2-thiophenecarboxylic acid to 400mL of chloroform solution, add 14.6g of N,N-dimethylformamide, and then add 640g of thionyl chloride, react at 35°C for 10h, and collect the fraction at 60°C by reduced pressure distillation to obtain 133.0g of 2-thiophenecarboxylic acid chloride; S3. Add 62.0 g of N-hydroxybenzamidine to 300 mL of toluene solution, add 76.5 g of potassium hydroxide and 73.5 g of 2-thiophenecarbonyl chloride in sequence, heat to 100 ° C for reaction for 6 h, cool to 5 ° C for crystallization for 2 h, filter out the solid, add to 200 mL of a mixed solution of n-hexane and chloroform (the volume ratio of n-hexane to chloroform is 1:1), recrystallize at 70 ° C for 2 h, filter, and dry to obtain 99.7 g of 3-phenyl-5-(thiophene-2-yl)-1,2,4-oxadiazole with a purity of 98.8% and a yield of 86.4%.
[0021] Example 3 The only difference between this embodiment and embodiment 1 is that in step S1 and step S3, the mixed solution of n-hexane and chloroform (the volume ratio of n-hexane to chloroform is 1:1) is replaced by a mixed solution of dimethyl carbonate and chloroform (the volume ratio of dimethyl carbonate to chloroform is 1:1).
[0022] Result: 99.6 g of 3-phenyl-5-(thiophen-2-yl)-1,2,4-oxadiazole was obtained with a purity of 98.6% and a yield of 86.1%.
[0023] Example 4 The only difference between this embodiment and Embodiment 1 is that in step S1 and step S3, the mixed solution of n-hexane and chloroform (the volume ratio of n-hexane to chloroform is 1:1) is replaced by a mixed solution of n-hexane and dimethyl carbonate (the volume ratio of n-hexane to dimethyl carbonate is 1:1).
[0024] Result: 102.0 g of 3-phenyl-5-(thiophen-2-yl)-1,2,4-oxadiazole was obtained with a purity of 98.9% and a yield of 88.5%.
[0025] Example 5 The only difference between this embodiment and embodiment 4 is that the volume ratio of n-hexane to dimethyl carbonate in step S1 is 10:1.
[0026] Result: 102.7 g of 3-phenyl-5-(thiophen-2-yl)-1,2,4-oxadiazole was obtained with a purity of 99.1% and a yield of 89.3%.
[0027] Example 6 The only difference between this embodiment and embodiment 4 is that the volume ratio of n-hexane to dimethyl carbonate in step S1 is 4:1.
[0028] Result: 105.0 g of 3-phenyl-5-(thiophen-2-yl)-1,2,4-oxadiazole was obtained with a purity of 99.2% and a yield of 91.4%.
[0029] Example 7 The only difference between this embodiment and embodiment 4 is that the volume ratio of n-hexane to dimethyl carbonate in step S1 is 8:1.
[0030] Result: 105.3 g of 3-phenyl-5-(thiophen-2-yl)-1,2,4-oxadiazole was obtained with a purity of 99.2% and a yield of 91.6%.
[0031] Example 8 The only difference between this embodiment and embodiment 7 is that the volume ratio of n-hexane to dimethyl carbonate in step S3 is 1:15.
[0032] Result: 106.4 g of 3-phenyl-5-(thiophen-2-yl)-1,2,4-oxadiazole was obtained with a purity of 99.4% and a yield of 92.8%.
[0033] Example 9 The only difference between this embodiment and embodiment 7 is that the volume ratio of n-hexane to dimethyl carbonate in step S3 is 1:5.
[0034] Result: 107.8 g of 3-phenyl-5-(thiophen-2-yl)-1,2,4-oxadiazole was obtained with a purity of 99.5% and a yield of 94.1%.
[0035] Example 10 The only difference between this embodiment and embodiment 7 is that the volume ratio of n-hexane to dimethyl carbonate in step S3 is 1:10.
[0036] Result: 107.8 g of 3-phenyl-5-(thiophen-2-yl)-1,2,4-oxadiazole was obtained with a purity of 99.6% and a yield of 94.2%.
[0037] Comparative Example 1 The only difference between this comparative example and Example 1 is that in step S1 and step S3, the mixed solution of n-hexane and chloroform (the volume ratio of n-hexane to chloroform is 1:1) is replaced by a mixed solution of ethyl acetate and chloroform (the volume ratio of ethyl acetate to chloroform is 1:1).
[0038] Result: 94.1 g of 3-phenyl-5-(thiophen-2-yl)-1,2,4-oxadiazole was obtained with a purity of 95.3% and a yield of 78.7%.
[0039] Comparative Example 2 The only difference between this comparative example and Example 1 is that in step S1 and step S3, the mixed solution of n-hexane and chloroform (the volume ratio of n-hexane to chloroform is 1:1) is replaced by a mixed solution of n-hexane and ethyl acetate (the volume ratio of n-hexane to ethyl acetate is 1:1).
[0040] Result: 93.0 g of 3-phenyl-5-(thiophen-2-yl)-1,2,4-oxadiazole was obtained with a purity of 94.2% and a yield of 76.9%.
[0041] Compared with Example 1, the composition of the recrystallization solvent was changed in Comparative Examples 1 and 2. As a result, the yield and purity of 3-phenyl-5-(thiophene-2-yl)-1,2,4-oxadiazole obtained in Comparative Examples 1 and 2 were lower than those in Example 1, indicating that when the recrystallization solvent consisted of n-hexane and chloroform, the yield and purity of 3-phenyl-5-(thiophene-2-yl)-1,2,4-oxadiazole could be improved.
[0042] Compared with Example 1, the composition of the recrystallization solvent was changed in Examples 3 and 4. As a result, the yield of 3-phenyl-5-(thiophen-2-yl)-1,2,4-oxadiazole obtained in Example 4 was higher than that in Example 1 and Example 3, indicating that when the recrystallization solvent consists of n-hexane and dimethyl carbonate, the yield of 3-phenyl-5-(thiophen-2-yl)-1,2,4-oxadiazole can be further improved.
[0043] Compared with Example 4, the volume ratio of n-hexane and dimethyl carbonate in step 1 was changed in Examples 5 to 7. As a result, the yield of 3-phenyl-5-(thiophene-2-yl)-1,2,4-oxadiazole obtained in Examples 6 to 7 was higher than that in Examples 4 and 5, indicating that when the volume ratio of n-hexane and dimethyl carbonate in step 1 was 4 to 8:1, the yield of 3-phenyl-5-(thiophene-2-yl)-1,2,4-oxadiazole could be further improved.
[0044] Compared with Example 7, the volume ratio of n-hexane and dimethyl carbonate in step 3 was changed in Examples 8 to 10. As a result, the yield of 3-phenyl-5-(thiophene-2-yl)-1,2,4-oxadiazole obtained in Examples 9 to 10 was higher than that in Examples 4 and 5, indicating that when the volume ratio of n-hexane and dimethyl carbonate in step 3 was 1:5 to 10, the yield of 3-phenyl-5-(thiophene-2-yl)-1,2,4-oxadiazole could be further improved.
[0045] The above are only preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the protection scope of the present invention.
Claims
1. A method for synthesizing 3-phenyl-5-(thiophene-2-yl)-1,2,4-oxadiazole, characterized in that: The following steps are involved: S1, using benzonitrile as a raw material, adding hydroxylamine hydrochloride, under the action of an alkaline acid binding agent, undergoing addition reaction, crystallization, and recrystallization to obtain N-hydroxybenzamidine; S2, using 2-thiophenecarboxylic acid as a raw material, in the presence of thionyl chloride and a catalyst, undergoing acylation reaction and distillation to obtain 2-thiophenecarboxylic acid chloride; S3, subjecting N-hydroxybenzamidine and 2-thiophenecarbonyl chloride to a basic substance, subjecting them to a cyclization reaction, crystallization, and recrystallization to obtain 3-phenyl-5-(thiophene-2-yl)-1,2,4-oxadiazole; The recrystallization solvents in step S1 and step S3 each independently include one or more of n-hexane, chloroform, and dimethyl carbonate.
2. The method for synthesizing 3-phenyl-5-(thiophen-2-yl)-1,2,4-oxadiazole according to claim 1, characterized in that: In step S1 and step S3, the recrystallization solvents independently include n-hexane and dimethyl carbonate.
3. The method for synthesizing 3-phenyl-5-(thiophene-2-yl)-1,2,4-oxadiazole according to claim 2, characterized in that: In step S1, the volume ratio of n-hexane to dimethyl carbonate is 4-8:
1.
4. The method for synthesizing 3-phenyl-5-(thiophene-2-yl)-1,2,4-oxadiazole according to claim 2, characterized in that: In step S3, the volume ratio of n-hexane to dimethyl carbonate is 1:5-10.
5. A method for synthesizing 3-phenyl-5-(thiophene-2-yl)-1,2,4-oxadiazole according to any one of claims 1 to 4, characterized in that: The alkaline acid-binding agent includes one or more of sodium carbonate, potassium carbonate and cesium carbonate.
6. A method for synthesizing 3-phenyl-5-(thiophene-2-yl)-1,2,4-oxadiazole according to any one of claims 1 to 4, characterized in that: The molar ratio of the benzonitrile, hydroxylamine hydrochloride and alkaline acid binding agent is 1:2:1.1-1.
3.
7. A method for synthesizing 3-phenyl-5-(thiophene-2-yl)-1,2,4-oxadiazole according to any one of claims 1 to 4, characterized in that: The catalyst is N,N-dimethylformamide; the molar ratio of the 2-thiophenecarboxylic acid to the catalyst is 1:0.1-0.2; and the mass ratio of the 2-thiophenecarboxylic acid to thionyl chloride is 1:4-5.
8. A method for synthesizing 3-phenyl-5-(thiophene-2-yl)-1,2,4-oxadiazole according to any one of claims 1 to 4, characterized in that: The solvent for the addition reaction includes one or more of methanol, ethanol, isopropanol, and ethyl acetate; the solvent for the acylation reaction includes one or two of dichloromethane and chloroform; and the solvent for the cyclization reaction includes one or more of butyl acetate, toluene, and methyl butyl ketone.
9. A method for synthesizing 3-phenyl-5-(thiophene-2-yl)-1,2,4-oxadiazole according to any one of claims 1 to 4, characterized in that: The alkaline substance includes one or more of lithium hydroxide, sodium hydroxide, and potassium hydroxide; the molar ratio of N-hydroxybenzamidine, 2-thenoyl chloride, and the alkaline substance is 1:1.1:2-3.
10. A method for synthesizing 3-phenyl-5-(thiophen-2-yl)-1,2,4-oxadiazole according to any one of claims 1 to 4, characterized in that: Include at least one of the following features: The temperature of the addition reaction is 40-50°C, and the time of the addition reaction is 6-7h; The temperature of the acylation reaction is 25-35°C, and the time of the acylation reaction is 10-15h; The temperature of the cyclization reaction is 80-100°C, and the time of the cyclization reaction is 6-7h; The distillation temperature is 60-65°C; The crystallization temperature in step S1 and step S3 is independently -5 to 5°C, and the crystallization time is independently 1 to 2 hours; The recrystallization temperatures in step S1 and step S3 are independently 50-70° C., and the recrystallization times are independently 2-3 hours.